Methods of Treatment Using Anti-IL-17A/F Antibodies

ABSTRACT

The invention relates to therapeutic uses of antibody molecules having specificity for antigenic determinants of both IL-17A and IL-17F in the treatment of dermatological and rheumatological diseases, such as psoriasis, psoriatic arthritis and axial spondyloarthritis.

CROSS-REFERENCE TO RELATED APPLICATIONS

The present application is a divisional application of U.S. applicationSer. No. 15/771,310, filed Nov. 16, 2018, which is a national phaseapplication of PCT/EP2016/075821, filed Oct. 26, 2016, and which claimsthe benefit of priority to U.S. Provisional Application No. 62/405,546,filed Oct. 7, 2016, U.S. Provisional Application No. 62/346,826, filedJun. 7, 2016, U.S. Provisional Application No. 62/303,230, filed Mar. 3,2016, and U.S. Provisional Application No. 62/246,989, filed Oct. 27,2015, the disclosures of which are incorporated herein by reference intheir entireties.

FIELD OF THE INVENTION

The application relates to antibody molecules having specificity forantigenic determinants of both IL-17A and IL-17F, as well as therapeuticuses of the antibody molecules.

INCORPORATION BY REFERENCE OF MATERIAL SUBMITTED ELECTRONICALLY

Incorporated by reference in its entirety is a computer-readablenucleotide/amino acid sequence listing submitted concurrently herewithand identified as follows: file name; “52958DIV_Seglisting.XML,” Size:56,919 bytes, created on Oct. 6, 2022.

BACKGROUND

Interleukin 17 (IL-17), also known as CTLA-8 or IL-17A, is apro-inflammatory cytokine which stimulates the secretion of a wide rangeof other cytokines from various non-immune cells. IL-17A is capable ofinducing the secretion of IL-6, IL-8, PGE2, MCP-1 and G-CSF by adherentcells like fibroblasts, keratinocytes, epithelial and endothelial cellsand is also able to induce ICAM-1 surface expression, proliferation of Tcells, and growth and differentiation of CD34+ human progenitors intoneutrophils when cocultured in the presence of irradiated fibroblasts(Fossiez et al., 1998, Int. Rev. Immunol. 16, 541-551). IL-17A ispredominantly produced by activated memory T cells and acts by bindingto a ubiquitously distributed cell surface receptor (IL-17R) (Yao etal., 1997, Cytokine, 9, 794-800). It may also act through binding to acomplex of IL-17RA and IL-17RC (Toy et al., 2006, J. Immunol. 177(11);36-39). IL-17 producing T cells called ‘TH17 cells’ have been implicatedin the pathogenesis of certain cancers (Weaver et al., 2006, Immunity,24, 677-688; Langowski et al., 2006, 442, 461-465; Iwakura and Ishigame,2006, J. Clin. Invest. 116, 5, 1218-1222).

A number of homologues of IL-17 have been identified which have bothsimilar and distinct roles in regulating inflammatory responses. For areview of IL-17 cytokine/receptor families see Dumont, 2003, ExpertOpin. Ther. Patents, 13, 287-303. One such homologue is IL-17F, alsoknown as IL-24 and ML-1, which has been reported as around 55% identicalto IL-17A and is thought to share the same receptors as IL-17A (Kollsand Linden 2004, Immunity, 21, 467-476; Hymowitz, et al., 2001, EMBO J.20(19), 5332-5341; Kuestner et al., 2007, Journal of Immunology, 179,5462-5473). While individual signalling molecules of IL-17A are morepotent than those of IL-17F, IL-17F has a greater impact in cooperationwith other molecules. For example, when IL-17F is added with TNFα to RAsynoviocytes, the induction of the potent inflammatory pathway issimilar to the response observed with IL-17A and TNFα. (Hot et al.,2011, Ann. Rheumatic Dis., 70, 341-348.)

IL-17A and IL-17F are expressed as homodimers, but may also be expressedas the IL-17A/F heterodimer (Wright et al. 2008, J. Immunol. 181:2799-2805). IL-17A and F signal through the receptors IL-17R, IL-17RC oran IL-17RA/RC receptor complex (Gaffen 2008, Cytokine. 43: 402-407).

IL-17A and IL-17F have been associated with dermatological andrheumatological conditions. Such dermatological conditions include, butare not limited to, psoriasis, atopic dermatitis, discoid lupuserythematosus, alopecia areata, autoimmune urticaria, bullouspemphigoid, dermatitis herpetiformis, hidradenitis suppurativa, linearIgA dermatosis, morphea, pemphigus vulgaris, and pyoderma gangrenosum.Such rheumatological conditions include psoriatic arthritis, axialspondyloarthritis including ankylosing spondylitis, systemic lupuserythematosus (SLE), rheumatoid arthritis, vasculitis, Sjogren'ssyndrome (extraglandular), juvenile idiopathic arthritis,granulomatosis, Behçet's disease (mucocutaneous), antiphospholipidsyndrome, giant cell arteritis, scleroderma, polyarteritis nodosa,Behçet's disease (thrombosis), and Takayasu disease.

Psoriatic arthritis is an inflammatory condition which affects both thejoints and the skin. It can lead to significant joint damage anddisability over time and can involve both skin and nail abnormalitiesseen in psoriasis. (Schett et al., 2011, Arthritis Research and Therapy,13 Suppl. 1: S4.) Psoriatic arthritis may be difficult to distinguishfrom other forms of arthritis, particularly when skin changes areminimal or absent. Psoriatic arthritis patients often experience anumber of other diseases at a higher frequency than the generalpopulation including autoimmune conditions such as iritis/uveitis(swelling and irritation of the eye) and inflammatory bowel disease(IBD), as well as cardiovascular disease and osteoporosis.

Psoriatic arthritis can negatively affect many aspects of a patient'slife, imposing burdens of pain, physical functioning and fatigue, aswell as reductions in psychological, emotional and social well-being andoverall health-related quality of life. (Husted et al., 2001, ArthritisCare and Research, 45:151-8; Picchianti-Diamani et al., 2010, Qual. LifeRes., 19:821-6.) Studies suggest many aspects of health-related qualityof life (HRQol) are affected to a similar degree in patients withpsoriatic arthritis and rheumatoid arthritis. (Husted et al., 2001,Arthritis Care and Research, 45:151-8). Psoriatic arthritis isassociated with a considerable economic burden, both in terms of directcosts (money spent on medication, hospital care, informal care andover-the-counter medication) and indirect costs (those associated with aloss of productivity at work). (Ackermann & Kavanaugh, 2008,Pharmacoeconomics, 26 (2):121-9).

Psoriatic arthritis can develop in individuals with psoriasis, aninflammatory disorder of the skin (Shbeeb et al., 2000, J Rheumatol.,27: 1247-50). Psoriatic arthritis typically develops in patients afterthe onset of psoriasis. (Gladman et al., 2006, Annuals of the RheumaticDiseases, 65 (Suppl. III): iii12-iii24). The mean age at which patientswith psoriatic arthritis are diagnosed is 41 years, with men oftendiagnosed at a younger age (20-39 years) than women (40-59 years).(Shbeed et al., 2000, J Rheumatol., 27:1247-50.) Between 3 and 8 peopleper 100,000 are newly diagnosed with psoriatic arthritis each year.(Gladman et al., 2005, Annuals of the Rheumatic Diseases, 64(Suppl II):ii14-ii17.)

Certain genes have been associated with psoriatic arthritis,particularly the HLA-B27 (human leukocyte antigen) gene, which ispresent in approximately 50% of psoriatic arthritis patients, comparedto just 3-18% of the Western European general population. (Gladman etal., 2005, Annuals of the Rheumatic Diseases, 64(Suppl II): ii14-ii17;Salvarani & Fries, 2009, World J. Gastroenterol., 15 (20): 2449-55.)

However, environmental factors may induce disease onset as well. Riskfactors associated with psoriatic arthritis include: psoriasis involvingthe scalp, intergluteal areas, more than 3 affected sites, naildystrophy, recent oral ulceration, and trauma leading to medical care.(Ogdie & Gelfand, 2010, Arch. Dermatol. 146(7):785-8; Pattison et al.,2008, Ann. Rheum. Dis., 67(5):672-6.)

There is a strong association between psoriasis, psoriatic arthritis andobesity. (Russolillo et al., 2013, J. Rheumatol., 52:62-67). In 80% ofpsoriatic arthritis cases, arthritis develops after the appearance ofpsoriasis.

Symptoms of psoriatic arthritis include, but are not limited, to:stiffness, pain, tenderness, swelling and throbbing in one or morejoints, usually in the hands or feet, but sometimes in the wrists,ankles, knee or lower back; swollen fingers or toes that may result in a“sausage-like” appearance (dactylitis); reduced ability to move; nailchanges, such as pitting or separation from the nail bed causingfunctional impairment, pain and emotional distress; eye redness and pain(uveitis); fatigue and morning stiffness (in affected joints);tenderness, pain and swelling over tendons (enthesitis); psoriaticarthritis may affect a small number of joints (oligoarthritis) or manyjoints (polyarthritis) and/or spine.

People with psoriatic arthritis symptoms, especially those withpsoriasis or a family history of psoriatic arthritis, need to see aspecialist (e.g. a rheumatologist), as their joint problems may besimilar to those seen in other forms of arthritis (e.g. rheumatoidarthritis, gout and reactive arthritis). (Conaghan & Coates, 2009, ThePractioner, 253(1724):15-18.) Diagnosis is based on symptoms, medicalhistory, physical examination, results of blood tests and X rays.(Conaghan & Coates, 2009, The Practioner, 253(1724); 15-18.)

Mild cases of psoriatic arthritis are usually treated with non-steroidalanti-inflammatory drugs (NSAIDs), low doses of oral steroids or steroidinjections into painful joints. (Mease, 2011, Ann. Rheum. Dis., 70(Suppl1):i77-i84.) More severe psoriatic arthritis is often treated withdisease-modifying anti-rheumatic drugs (DMARDs). (Weger, 2010, BritishJournal of Pharmacology, 160:810-20.) More recently, biological agentsincluding anti-tumour necrosis factor alpha antibodies (TNFα blockers)have become available. (Weger, 2010, British Journal of Pharmacology,160:810-20.) Clinical evidence has demonstrated that minimal diseaseactivity was achieved in 64% of patients treated with TNF-inhibitors,which means that a considerable portion of patients (36%) did notachieve even this target. (Haddad A et al, Arthritis Care Res. 2015; 67,842-7).

Some subjects are not responsive to previously known treatments, do notmaintain a clinical response (defined as achieving American College ofRheumatology 20% response criteria (“ACR20”), or have contraindicationsor intolerance to these agents. The availability of effective medicinesfor psoriatic arthritis that have an alternative mechanism of actionwill improve the treatment of patients, especially those patients whohave not gained benefit from, lost effectiveness to, or could not useTNF-inhibitor medications for safety or tolerability reasons. (Mease P,Curr Opin Rheumatol. 2015, 27: 127-33). Because ACR score is a scalethat measures symptoms such as joint effects associated with psoriaticarthritis and rheumatoid arthritis, improvements in ACR score areassociated with the treatment of both psoriatic arthritis and rheumatoidarthritis.

Breakthroughs in the understanding of immunopathogenesis of psoriaticarthritis have led to novel therapies beyond TNF-inhibitors. Thesetherapies are reviewed in Sritheran and Ying Leung, Ther. Adv.Musculoskel. Dis., 2015, 7(5), 173-186). Table 1 of this paper sets outthe ACR and PASI scores for the various therapies.

Drugs that inhibit IL-17 and IL-23 have demonstrated significant benefitin psoriasis and emerging studies are also showing benefit in psoriaticarthritis and ankylosing spondylitis. (Mease P, Curr Opin Rheumatol2015, 27: 127-33). Biological therapies are being developed which targetIL-17A, including the anti-IL-17A antibodies secukinumab and ixekizumabwhich are currently in Phase III clinical trials for psoriaticarthritis. The results of a Phase II clinical study of secukinumab inpsoriatic arthritis are described in Mease et al., 2015, N Engl J Med,373, 14, 1329-1339 and in ankylosing spondylitis in Baeten et al., N.Engl. J. Med, 2015, 373 (26), 2534-48. The results of a Phase IIIclinical study of ixekizumab in psoriatic arthritis are described inMease et al, 2015, ACR Abstract number 977. Brodalumab is an antiIL-17RA monoclonal antibody which, by targeting IL-17RA, blocks IL-17A,IL-17F and IL-17E (IL-25) activity. The results of a Phase II clinicalstudy of brodalumab in psoriatic arthritis are described in Mease etal., 2015, N Engl J Med, 370, 24, 2295-2306. The efficacy of currenttherapies at week 24 is around 60%, 40% and 20% for ACR20, ACR50 andACR70 respectively, along with a PASI 75 of around 65% (Table 1 inSritheran and Ying Leung, Ther. Adv. Musculoskel. Dis., 2015, 7(5),173-186).

SUMMARY OF THE INVENTION

The invention relates to antibody molecules having specificity forantigenic determinants of both IL-17A and IL-17F, therapeutic uses ofthe antibody molecules in the treatment of dermatological andrheumatological diseases, such as psoriatic arthritis, and methods forproducing said antibody molecules. In one example, the antibody of theinvention may be used in the treatment of dermatological conditions(such as, but not limited to, psoriasis, atopic dermatitis, discoidlupus erythematosus, alopecia areata, autoimmune urticaria, bullouspemphigoid, dermatitis herpetiformis, hidradenitis suppurativa, linearIgA dermatosis, morphea, pemphigus vulgaris, and pyoderma gangrenosum)and/or rheumatological conditions (such as, but not limited to psoriaticarthritis, axial spondyloarthritis including non-radiographic axialspondyloarthritis and ankylosing spondylitis, systemic lupuserythematosus (SLE), rheumatoid arthritis, vasculitis, Sjogren'ssyndrome (extraglandular), juvenile idiopathic arthritis,granulomatosis, Behçet's disease (mucocutaneous), antiphospholipidsyndrome, giant cell arteritis, scleroderma, polyarteritis nodosa,Behçet's disease (thrombosis), and Takayasu disease). In one example,the antibody of the invention may be used in the treatment of psoriaticarthritis. Neutralising antibodies which bind both IL-17A and IL-17F,such as bimekizumab, may provide a significant improvement over existingpsoriatic arthritis therapies, both in the speed and magnitude ofclinical effect. For example, they may mediate equivalent or evenimproved clinical scores by week 8. Suitable clinical scores includeAmerican College of Rheumatology (“ACR”) 20/50/70 response for jointsand, for skin, the clinical features of psoriasis, Psoriasis Area andSeverity Index (“PASI”) 50/75/90 response. For example, these antibodiesmay increase the number of patients achieving ACR20, ACR50, ACR70 andPASI75 at week 8 or week 12 to greater than 60%, 40%, 20% and 65%respectively (average response rate). They may even have the potentialto increase the number of patients achieving ACR20, ACR50, ACR70 andPASI75 at week 8 or week 12 to 60-95%, 40-60%, 20-40% and 80-100%respectively. For example these may be 80%, 60%, 40% and close to 90% orclose to 100% respectively. The speed to achieving a beneficial responsein subjects administered an antibody as described herein also isremarkable. For example, in various embodiments, the subject achievesACR20 or ACR50 (or PASI 20 or PASI50) within four weeks (e.g., withinthree weeks or within two weeks) of a first administration.Additionally, in various embodiments, the beneficial response to themethods described herein may be sustained for a remarkable period oftime. For instance, subjects administered three doses of anti-IL-17A/Fantibody described herein (e.g., at days 0, 21, and 42) enjoyed nearmaximal-response to week 20. Thus in various aspects, the methodsdescribed herein may achieve a biological response in a subject at week8 or week 12 that diminishes no more than 10%, no more than 20%, no morethan 30%, no more than 40%, or no more than 50% at week 20. In oneexample, the antibody of the invention may be used in the treatment ofany of the symptoms of psoriatic arthritis listed herein below,including but not limited to dactylitis, enthesitis, nail dystrophy,skin manifestations; signs and symptoms of peripheral arthritis; axialdisease and structural progression of the disease. In one example, theantibody of the invention may be used to prevent the development ofpsoriatic arthritis or other conditions in psoriasis patients.

The invention further provides the use of an antibody molecule accordingto the invention in the manufacture of a medicament for the treatment orprophylaxis of a pathological disorder that is mediated by IL-17A and/orIL-17F or associated with an increased level of IL-17A and/or IL-17F.Preferably the pathological disorder may be one of the medicalindications described herein. In one embodiment, the pathologicaldisorder may comprise psoriatic arthritis. In other embodiments, thepathological disorder may comprise psoriasis, rheumatoid arthritis,and/or arthritis. In various embodiments, the pathological disorder isankylosing spondylitis. In various embodiments, the pathologicaldisorder is axial spondyloarthritis or non-radiographic axialspondyloarthritis.

An antibody molecule of the invention may be utilised in any therapywhere it is desired to reduce the effects of IL-17A and/or IL-17F in thehuman or animal body. IL-17A and/or IL-17F may be circulating in thebody or may be present in an undesirably high level localised at aparticular site in the body, for example a site of inflammation.

In one embodiment, the invention provides a method of treating human oranimal subjects suffering from or at risk of a disorder mediated byIL-17A and/or IL-17F, the method comprising administering to the subjectan effective amount of an antibody molecule of the invention.

In one embodiment, the invention also provides an antibody molecule ofthe invention, in particular a neutralising antibody which binds humanIL-17A and human IL-17F, for use in the treatment of human or animalsubjects suffering from or at risk of a disorder mediated by IL-17Aand/or IL-17F. Preferably the pathological disorder may be one of themedical indications described herein. In one embodiment, thepathological disorder may comprise psoriatic arthritis. In otherembodiments, the pathological disorder may comprise psoriasis,rheumatoid arthritis, and/or arthritis. In one embodiment thepathological disorder may comprise ankylosing spondylitis. In oneembodiment the pathological disorder may comprise axialspondyloarthritis or non-radiographic axial spondyloarthritis.

In one embodiment, the invention therefore provides an antibody moleculeof the invention, in particular a neutralising antibody which bindshuman IL-17A and human IL-17F, for use in the treatment of psoriaticarthritis, psoriasis, rheumatoid arthritis, arthritis, axialspondyloarthritis, ankylosing spondylitis or non-radiographic axialspondyloarthritis. “Psoriasis” encompasses disorders or skin-relatedcomponents (i.e., symptoms) of disorders such as, but not limited to,plaque psoriasis, pustular psoriasis, generalised pustular psoriasis,palmo-plantar psoriasis, scalp psoriasis, guttate psoriasis,erythrodermic psoriasis, inversive psoriasis, acrodermatitis continua,SAPHO (Synovitis, Acne, Pustulosis, Hyperostosis and Osteitis) syndrome,hidradenitis suppurativa, and DITRA (deficiency of the IL-36 receptor[IL-36R] antagonist)/DIRA (deficiency of the interleukin 1 (IL-1)receptor antagonist). The severity of psoriasis may vary and may beselected, for example, from mild, mild to moderate, moderate, severe andmoderate to severe psoriasis.

An antibody molecule according to the invention may also be used indiagnosis, for example in the in vivo diagnosis and imaging of diseasestates involving IL-17A and/or IL-17F.

The invention provides a method of treating psoriatic arthritis in ahuman comprising the step of administering to the human a neutralizingantibody which binds human IL-17A and human IL-17F. In an embodiment,the antibody specifically binds an epitope of human IL-17F, the epitopecomprising one or more residues selected from ARG47, ARG73, LEU75 andILE86 of SEQ ID NO: 27. In the same or a different embodiment, theantibody specifically binds an epitope of human IL-17A, the epitopecomprising one or more residues selected from TYR44, ASN45, ARG46,TRP51, ASN52, HIS54 and ASP84 of SEQ ID NO: 28. In various embodiments,the antibody binds to the same epitope on human IL-17A, human IL-17F, orIL-17 A/F heterodimer as a neutralising antibody that has a heavy chaincomprising the sequence given in SEQ ID NO: 11 and a light chaincomprising the sequence given in SEQ ID NO: 10. Optionally, the antibodycross-blocks a neutralising antibody that has a heavy chain comprisingthe sequence given in SEQ ID NO: 11 and a light chain comprising thesequence given in SEQ ID NO: 10 and binds human IL-17A and human IL-17F.In various embodiments, the antibody comprises a light chain variabledomain and a heavy chain variable domain, wherein the variable domain ofthe light chain comprises the sequence given in SEQ ID NO:10. In oneaspect, the antibody is bimekizumab. Optionally, the antibody isadministered as a pharmaceutical composition. In various embodiments,the antibody is administered subcutaneously or intravenously.

In any of the embodiments of the method of treating psoriatic arthritisin a human comprising the step of administering to the human aneutralizing antibody which binds human IL-17A and human IL-17F, thehuman optionally has a diagnosis of adult-onset psoriatic arthritis.Optionally, the human is at least 18 years of age and/or was diagnosedat least six months prior to administration of the antibody. Alsooptionally, the human was diagnosed based on the CASPAR criteria. In anyof the embodiments described above, the human has active arthritis. Thisis typically defined as ≥3 tender and ≥3 swollen joints. The patientsmay have coexistent or concomitant psoriasis and/or a history ofpsoriasis. For example, the human optionally has active psoriaticlesions or a history of psoriatic lesions.

In any of the embodiments of the method of treating psoriatic arthritis,psoriasis, rheumatoid arthritis or axial spondylitis, includingankylosing spondylitis and non-radiographic spondylitis in a humancomprising the step of administering to the human a neutralizingantibody which binds human IL-17A and human IL-17F described herein, theantibody may be administered as a monotherapy.

In any of the embodiments of the method of treating psoriatic arthritis,psoriasis, rheumatoid arthritis or axial spondlyitis, includingankylosing spondylitis and non-radiographic spondylitis in a humancomprising the step of administering to the human a neutralizingantibody which binds human IL-17A and human IL-17F described herein, thehuman optionally is biologic-naïve i.e. has not been previously treatedwith a biological agent, such as a TNF alpha inhibitor such as ananti-TNF antibody.

In any of the embodiments of the method of treating psoriatic arthritisin a human comprising the step of administering to the human aneutralizing antibody which binds human IL-17A and human IL-17Fdescribed herein, the human optionally is an inadequate responder to atleast one non-biologic disease-modifying antirheumatic drug (“DMARD”)and/or one or more approved biologic DMARD (e.g., a TNF inhibitor suchas an anti-TNF antibody, examples including inflixumab or adalimumab, ora soluble TNF receptor, such as etanercept). Examples of non-biologicDMARDs include sulfsalazine, methotrexate, cyclosporine,hydrozychloroquine, azathioprine and leflunomide. Optionally the humanis an inadequate responder to at least one non-steroidalanti-inflammatory drug (NSAID). Examples of suitable NSAIDs include butare not limited to, propionic acid derivative, acetic acid derivative,enolic acid derivatives, fenamic acid derivatives, cox inhibitors,ibuprofen, fenoprofen and aspirin.

The invention also provides a method of treating psoriatic arthritis ina human concurrently treated with methotrexate or other non-biologicDMARD (such as leflunomide) or non-steroidal anti-inflammatory drug(NSAID) and/or steroid comprising the step of administering to the humana neutralizing antibody which binds human IL-17A and human IL-17F. Invarious embodiments, the antibody specifically binds an epitope of humanIL-17F, the epitope comprising one or more residues selected from ARG47,ARG73, LEU75 and ILE86 of SEQ ID NO: 27. In the same or differentembodiments, the antibody specifically binds an epitope of human IL-17A,the epitope comprising one or more residues selected from TYR44, ASN45,ARG46, TRP51, ASN52, HIS54 and ASP84 of SEQ ID NO: 28. Optionally, theantibody binds to the same epitope on human IL-17A, human IL-17F, orIL-17 A/F heterodimer as a neutralising antibody that has a heavy chaincomprising the sequence given in SEQ ID NO: 11 and a light chaincomprising the sequence given in SEQ ID NO: 10. Also optionally, theantibody cross-blocks a neutralising antibody that has a heavy chaincomprising the sequence given in SEQ ID NO: 11 and a light chaincomprising the sequence given in SEQ ID NO: 10 and binds human IL-17Aand human IL-1 7F. In various aspects of the method, the antibodycomprises a light chain variable domain and a heavy chain variabledomain, wherein the variable domain of the light chain comprises thesequence given in SEQ ID NO:10. In a preferred embodiment, the antibodyis bimekizumab. The antibody may be administered as a pharmaceuticalcomposition. The antibody is optionally administered subcutaneously orintravenously.

The invention includes a method of treating psoriatic arthritis in ahuman comprising the step of administering to the human atherapeutically effective amount of a neutralizing antibody which bindshuman IL-17A and human IL-17F. In various aspects, the antibodyspecifically binds an epitope of human IL-17F, the epitope comprisingone or more residues selected from ARG47, ARG73, LEU75 and ILE86 of SEQID NO: 27. In the same or different aspects, the antibody specificallybinds an epitope of human IL-17A, the epitope comprising one or moreresidues selected from TYR44, ASN45, ARG46, TRP51, ASN52, HIS54 andASP84 of SEQ ID NO: 28. Optionally, the antibody binds to the sameepitope on human IL-17A, human IL-17F, or IL-17 A/F heterodimer as aneutralising antibody that has a heavy chain comprising the sequencegiven in SEQ ID NO: 11 and a light chain comprising the sequence givenin SEQ ID NO: 10. In various embodiments, the antibody cross-blocks aneutralising antibody that has a heavy chain comprising the sequencegiven in SEQ ID NO: 11 and a light chain comprising the sequence givenin SEQ ID NO: 10 and binds human IL-1 7A and human IL-1 7F. Theantibody, in various embodiments, comprises a light chain variabledomain and a heavy chain variable domain, wherein the variable domain ofthe light chain comprises the sequence given in SEQ ID NO:10. In apreferred embodiment, the antibody is bimekizumab. The antibody isoptionally administered as a pharmaceutical composition. The antibodymay be administered subcutaneously or intravenously.

An embodiment of the invention includes a method of treating psoriaticarthritis in a human patient comprising the step of administering to thepatient a neutralizing antibody which binds human IL-17A and humanIL-17F in an amount that is effective to provide an ACR20 response atweek 8 or week 12, an ACR50 response at week 8 or week 12, or an ACR70response at week 8 or week 12 in a population of patients in need oftreatment. For example, the administered amount is effective to providean ACR50 response at week 8 or week 12, or an ACR70 response at week 8or week 12 in the population of patients. In a preferred aspect, theamount is effective to provide an ACR70 response at week 8 or week 12 inthe population of patients. Alternatively or in addition, theneutralizing antibody is administered in an amount that is effective toprovide a PASI50 response at week 8 or week 12, PASI75 response at week8 or week 12, or a PASI90 response at week 8 or week 12, such as anamount that is effective to provide a PASI75 response at week 8 or week12, or a PASI90 response at week 8 or week 12 in the population ofpatients. In a preferred aspect, the neutralizing antibody isadministered in an amount that is effective to provide a PASI90 responseor a PASI100 response at week 8 or week 12 in the population ofpatients. Typically the response is sustained such that ACR50, ACR70and/or PASI responses may be maintained to week 16, 20, 24 or later. Invarious aspects, the antibody specifically binds an epitope of humanIL-17F, the epitope comprising one or more residues selected from ARG47,ARG73, LEU75 and ILE86 of SEQ ID NO: 27 and/or specifically binds anepitope of human IL-17A, the epitope comprising one or more residuesselected from TYR44, ASN45, ARG46, TRP51, ASN52, HIS54 and ASP84 of SEQID NO: 28. In various aspects, the antibody binds to the same epitope onhuman IL-17A, human IL-17F, or IL-17 A/F heterodimer as a neutralisingantibody that has a heavy chain comprising the sequence given in SEQ IDNO: 11 and a light chain comprising the sequence given in SEQ ID NO: 10.In various aspects, the antibody cross-blocks a neutralising antibodythat has a heavy chain comprising the sequence given in SEQ ID NO: 11and a light chain comprising the sequence given in SEQ ID NO: 10 andbinds human IL-1 7A and human IL-1 7F. Optionally, the antibodycomprises a light chain variable domain and a heavy chain variabledomain, wherein the variable domain of the light chain comprises thesequence given in SEQ ID NO:10. In a preferred aspect, the antibody isbimekizumab. The antibody is optionally administered as a pharmaceuticalcomposition. The antibody may be administered subcutaneously orintravenously.

The invention further provides a method of reducing psoriasis in a humancomprising the step of administering to the human a neutralizingantibody which binds human IL-17A and human IL-17F. In variousembodiments, the psoriasis is plaque psoriasis. In various embodimentsthe psoriasis is mild to moderate plaque psoriasis. In variousembodiments the psoriasis is moderate to severe plaque psoriasis. Thereduction of plaque psoriasis is optionally measured by PASI criteria.In various embodiments, the antibody specifically binds an epitope ofhuman IL-17F, the epitope comprising one or more residues selected fromARG47, ARG73, LEU75 and ILE86 of SEQ ID NO: 27. Alternatively or inaddition, the antibody specifically binds an epitope of human IL-17A,the epitope comprising one or more residues selected from TYR44, ASN45,ARG46, TRP51, ASN52, HIS54 and ASP84 of SEQ ID NO: 28. In variousaspects, the antibody binds to the same epitope on human IL-17A, humanIL-17F, or IL-17 A/F heterodimer as a neutralising antibody that has aheavy chain comprising the sequence given in SEQ ID NO: 11 and a lightchain comprising the sequence given in SEQ ID NO: 10. Optionally, theantibody cross-blocks a neutralising antibody that has a heavy chaincomprising the sequence given in SEQ ID NO: 11 and a light chaincomprising the sequence given in SEQ ID NO: 10 and binds human IL-1 7Aand human IL-1 7F. In various embodiments, the antibody comprises alight chain variable domain and a heavy chain variable domain, whereinthe variable domain of the light chain comprises the sequence given inSEQ ID NO:10. In a preferred aspect, the antibody is bimekizumab. Theantibody may be administered as a pharmaceutical composition. Theantibody is optionally administered subcutaneously or intravenously. Inone or more embodiments, the psoriasis treated using the method of thepresent invention may be selected from plaque psoriasis, pustularpsoriasis, generalised pustular psoriasis, palmo-plantar psoriasis, nailpsoriasis, scalp psoriasis, guttate psoriasis, erythrodermic psoriasis,inversive psoriasis.

The invention also includes a method of treating psoriasis in a humancomprising the step of administering to the human a therapeuticallyeffective amount of a neutralizing antibody which binds human IL-17A andhuman IL-17F.

The invention further provides a method of treating psoriasis in a humanpatient comprising the step of administering to the patient aneutralizing antibody which binds human IL-17A and human IL-17F in anamount that is effective to provide a PASI75 response at week 8 or week12, or a PASI90 response at week 8 or week 12. In a preferred aspect,the neutralizing antibody is administered in an amount that is effectiveto provide a PASI75 response or a PASI90 response at week 8 or week 12in the population of patients. In various aspects, the antibodyspecifically binds an epitope of human IL-17F, the epitope comprisingone or more residues selected from ARG47, ARG73, LEU75 and ILE86 of SEQID NO: 27 and/or specifically binds an epitope of human IL-17A, theepitope comprising one or more residues selected from TYR44, ASN45,ARG46, TRP51, ASN52, HIS54 and ASP84 of SEQ ID NO: 28. In variousaspects, the antibody binds to the same epitope on human IL-17A, humanIL-17F, or IL-17 A/F heterodimer as a neutralising antibody that has aheavy chain comprising the sequence given in SEQ ID NO: 11 and a lightchain comprising the sequence given in SEQ ID NO: 10. In variousaspects, the antibody cross-blocks a neutralising antibody that has aheavy chain comprising the sequence given in SEQ ID NO: 11 and a lightchain comprising the sequence given in SEQ ID NO: 10 and binds humanIL-1 7A and human IL-1 7F. Optionally, the antibody comprises a lightchain variable domain and a heavy chain variable domain, wherein thevariable domain of the light chain comprises the sequence given in SEQID NO:10. In a preferred aspect, the antibody is bimekizumab. Theantibody is optionally administered as a pharmaceutical composition. Theantibody may be administered subcutaneously or intravenously.

The method of treating psoriasis optionally comprises administering tothe human a loading dose of the neutralizing antibody followed by atleast one maintenance dose of the antibody. In various embodiments, theloading dose is between 80 and 560 mg and the at least one maintenancedose is between 40 and 320 mg. In one aspect of the method, the loadingdose is 80 mg and the at least one maintenance dose is 40 mg. In anotheraspect of the method, the loading dose is 160 mg and the at least onemaintenance dose is 80 mg. In a further aspect, the loading dose is 240mg and the at least one maintenance dose is 160 mg. In a further aspect,the loading dose is 320 mg and the at least one maintenance dose is 160mg. In another aspect, the loading dose is 560 mg and the at least onemaintenance dose is 320 mg. In various embodiments, the loading dose isadministered followed by two maintenance doses. Optionally, the loadingdose is administered followed by at least one maintenance dose at athree week interval or a four week interval.

In any of the embodiments of the method of treating psoriasis in a humancomprising the step of administering to the human a neutralizingantibody which binds human IL-17A and human IL-17F described herein, thehuman optionally is an inadequate responder to at least one non-biologicdisease-modifying antirheumatic drug (“DMARD”) and/or one or moreapproved biologic DMARD (e.g., a TNF inhibitor such as an anti-TNFantibody, examples including inflixumab or adalimumab, or a soluble TNFreceptor, such as etanercept). Examples of non-biologic DMARDs includesulfsalazine, methotrexate, cyclosporine, hydrozychloroquine,azathioprine and leflunomide. Optionally the human is an inadequateresponder to at least one non-steroidal anti-inflammatory drug (NSAID).Examples of suitable NSAIDs include but are not limited to, propionicacid derivative, acetic acid derivative, enolic acid derivatives,fenamic acid derivatives, cox inhibitors, ibuprofen, fenoprofen andaspirin.

The invention also provides a method of treating psoriasis in a humanconcurrently treated with methotrexate or other non-biologic DMARD (suchas leflunomide) or non-steroidal anti-inflammatory drug (NSAID) and/orsteroid comprising the step of administering to the human a neutralizingantibody which binds human IL-17A and human IL-17F.

The invention also provides a method of reducing joint effects in ahuman comprising the step of administering to the human a neutralizingantibody which binds human IL-17A and human IL-17F. The reduction ofjoint effects is optionally measured by ACR criteria. In variousaspects, the antibody specifically binds an epitope of human IL-17F, theepitope comprising one or more residues selected from ARG47, ARG73,LEU75 and ILE86 of SEQ ID NO: 27. Alternatively or in addition, theantibody specifically binds an epitope of human IL-17A, the epitopecomprising one or more residues selected from TYR44, ASN45, ARG46,TRP51, ASN52, HIS54 and ASP84 of SEQ ID NO: 28. In various aspects, theantibody binds to the same epitope on human IL-17A, human IL-17F, orIL-17 A/F heterodimer as a neutralising antibody that has a heavy chaincomprising the sequence given in SEQ ID NO: 11 and a light chaincomprising the sequence given in SEQ ID NO: 10. In various aspects, theantibody cross-blocks a neutralising antibody that has a heavy chaincomprising the sequence given in SEQ ID NO: 11 and a light chaincomprising the sequence given in SEQ ID NO: 10 and binds human IL-1 7Aand human IL-1 7F. Optionally, the antibody comprises a light chainvariable domain and a heavy chain variable domain, wherein the variabledomain of the light chain comprises the sequence given in SEQ ID NO:10.In a preferred aspect, the antibody is bimekizumab. The antibody may beadministered as a pharmaceutical composition. The antibody is optionallyadministered subcutaneously or intravenously. Such joint effects mayalso include peripheral joint involvement, including synovitis,enthesitis and/or dactylitis.

The invention provides a method of reducing psoriasis and reducing jointeffects in a human comprising the step of administering to the human aneutralizing antibody which binds human IL-17A and human IL-17F. Invarious embodiments, the psoriasis is plaque psoriasis. The reduction ofplaque psoriasis is optionally measured by PASI criteria and/or thereduction of joint effects is optionally measured by ACR criteria.Alternatively or in addition, the reduction of joint effects, such asstructural progression, may be measured by modified total sharp score(mTSS). Where measured, a reduction in enthesitis or dactylitis may bemeasured by a reduction in Leeds enthesitis index (LEI) and Leedsdactylitis index (LDI) scores respectively. In various aspects, theantibody specifically binds an epitope of human IL-17F, the epitopecomprising one or more residues selected from ARG47, ARG73, LEU75 andILE86 of SEQ ID NO: 27. Alternatively or in addition, the antibodyspecifically binds an epitope of human IL-17A, the epitope comprisingone or more residues selected from TYR44, ASN45, ARG46, TRP51, ASN52,HIS54 and ASP84 of SEQ ID NO: 28. In various aspects, the antibody bindsto the same epitope on human IL-17A, human IL-17F, or IL-17 A/Fheterodimer as a neutralising antibody that has a heavy chain comprisingthe sequence given in SEQ ID NO: 11 and a light chain comprising thesequence given in SEQ ID NO: 10. In various aspects, the antibodycross-blocks a neutralising antibody that has a heavy chain comprisingthe sequence given in SEQ ID NO: 11 and a light chain comprising thesequence given in SEQ ID NO: 10 and binds human IL-17A and human IL-17F. Optionally, the antibody comprises a light chain variable domain anda heavy chain variable domain, wherein the variable domain of the lightchain comprises the sequence given in SEQ ID NO:10. In a preferredaspect, the antibody is bimekizumab. The antibody may be administered asa pharmaceutical composition. The antibody is optionally administeredsubcutaneously or intravenously.

The invention further provides a method of treating psoriatic arthritisin a human, comprising the step of administering to the human a loadingdose of a neutralizing antibody which binds human IL-17A and humanIL-17F followed by at least one maintenance dose of the antibody.Optionally, the loading dose is between 80 and 560 mg and the at leastone maintenance dose is between 40 and 320 mg. In one aspect of themethod, the loading dose is 80 mg and the at least one maintenance doseis 40 mg. In another aspect of the method, the loading dose is 160 mgand the at least one maintenance dose is 80 mg. In a further aspect, theloading dose is 240 mg and the at least one maintenance dose is 160 mg.In a further aspect, the loading dose is 320 mg and the at least onemaintenance dose is 160 mg. In another aspect, the loading dose is 560mg and the at least one maintenance dose is 320 mg. In variousembodiments, the loading dose is administered followed by twomaintenance doses. Optionally, the loading dose is administered followedby at least one maintenance dose at a three week interval or a four weekinterval. The antibody, in various embodiments, specifically binds anepitope of human IL-17F, the epitope comprising one or more residuesselected from ARG47, ARG73, LEU75 and ILE86 of SEQ ID NO: 27.Alternatively or in addition, the antibody specifically binds an epitopeof human IL-17A, the epitope comprising one or more residues selectedfrom TYR44, ASN45, ARG46, TRP51, ASN52, HIS54 and ASP84 of SEQ ID NO:28. In various aspects, the antibody binds to the same epitope on humanIL-17A, human IL-17F, or IL-17 A/F heterodimer as a neutralisingantibody that has a heavy chain comprising the sequence given in SEQ IDNO: 11 and a light chain comprising the sequence given in SEQ ID NO: 10.In various aspects, the antibody cross-blocks a neutralising antibodythat has a heavy chain comprising the sequence given in SEQ ID NO: 11and a light chain comprising the sequence given in SEQ ID NO: 10 andbinds human IL-17A and human IL-1 7F. In various aspects, the antibodycomprises a light chain variable domain and a heavy chain variabledomain, wherein the variable domain of the light chain comprises thesequence given in SEQ ID NO:10. In a preferred aspect, the antibody isbimekizumab. The antibody may be administered as a pharmaceuticalcomposition. The antibody is optionally administered subcutaneously orintravenously.

An embodiment of the invention may include a method of treatingpsoriatic arthritis in a human, comprising the step of administering tothe human at least one dose of a neutralizing antibody which binds humanIL-17A and human IL-17F. In various embodiments, at least one dose isbetween 40 and 640 mg of the antibody. For example, in various aspects,at least one dose is 40 mg of the antibody. In various aspects, at leastone dose is 80 mg of the antibody. In various aspects, at least one doseis 160 mg of the antibody. In various aspects, at least one dose is 240mg of the antibody. In various aspects, at least one dose is 320 mg ofthe antibody. In various aspects, at least one dose is 480 mg of theantibody. In various aspects, at least one dose is 560 mg of theantibody. In various aspects, at least one dose is 640 mg of theantibody. In any of the aspects, the doses are optionally administeredat a three week interval or a four week interval. In any of the aspects,the doses are optionally administered at an eight week interval or atwelve week interval. In any of the aspects, the antibody specificallybinds an epitope of human IL-17F, the epitope comprising one or moreresidues selected from ARG47, ARG73, LEU75 and ILE86 of SEQ ID NO: 27.Alternatively or in addition, the antibody specifically binds an epitopeof human IL-17A, the epitope comprising one or more residues selectedfrom TYR44, ASN45, ARG46, TRP51, ASN52, HIS54 and ASP84 of SEQ ID NO:28. In various aspects, the antibody binds to the same epitope on humanIL-17A, human IL-17F, or IL-17 A/F heterodimer as a neutralisingantibody that has a heavy chain comprising the sequence given in SEQ IDNO: 11 and a light chain comprising the sequence given in SEQ ID NO: 10.In various aspects, the antibody cross-blocks a neutralising antibodythat has a heavy chain comprising the sequence given in SEQ ID NO: 11and a light chain comprising the sequence given in SEQ ID NO: 10 andbinds human IL-1 7A and human IL-1 7F. Optionally, the antibodycomprises a light chain variable domain and a heavy chain variabledomain, wherein the variable domain of the light chain comprises thesequence given in SEQ ID NO:10. In a preferred aspect, the antibody isbimekizumab. The antibody may be administered as a pharmaceuticalcomposition. The antibody is optionally administered subcutaneously orintravenously.

The invention also provides a method of treating rheumatoid arthritis ina human comprising the step of administering to the human a neutralizingantibody which binds human IL-17A and human IL-17F. In various aspects,the antibody specifically binds an epitope of human IL-17F, the epitopecomprising one or more residues selected from ARG47, ARG73, LEU75 andILE86 of SEQ ID NO: 27. Alternatively or in addition, the antibodyspecifically binds an epitope of human IL-17A, the epitope comprisingone or more residues selected from TYR44, ASN45, ARG46, TRP51, ASN52,HIS54 and ASP84 of SEQ ID NO: 28. In various embodiments, the antibodybinds to the same epitope on human IL-17A, human IL-17F, or IL-17 A/Fheterodimer as a neutralising antibody that has a heavy chain comprisingthe sequence given in SEQ ID NO: 11 and a light chain comprising thesequence given in SEQ ID NO: 10. Optionally, the antibody cross-blocks aneutralising antibody that has a heavy chain comprising the sequencegiven in SEQ ID NO: 11 and a light chain comprising the sequence givenin SEQ ID NO: 10 and binds human IL-1 7A and human IL-1 7F. In variousembodiments, the antibody comprises a light chain variable domain and aheavy chain variable domain, wherein the variable domain of the lightchain comprises the sequence given in SEQ ID NO:10. In a preferredaspect, the antibody is bimekizumab. The antibody may be administered asa pharmaceutical composition. The antibody is optionally administeredsubcutaneously or intravenously.

In various embodiments of the method of treating rheumatoid arthritis ina human, the human has a diagnosis of adult-onset rheumatoid arthritis;optionally, the human is at least 18 years of age. Also optionally, thehuman was diagnosed at least six months prior to administration of theantibody. In various embodiments, the human was classified based on theACR/EULAR 2010 criteria. In various embodiments of the method oftreating rheumatoid arthritis in a human, the human has activearthritis. In various aspects of the method of treating rheumatoidarthritis in a human, the human is an inadequate responder to at leastone non-biologic disease-modifying antirheumatic drug (“DMARD”) and/orat least one approved biologic DMARD. Alternatively, or in addition, thehuman may be an inadequate responder to at least one non-steroidalanti-inflammatory drug (NSAID).

The invention provides a method of treating rheumatoid arthritis in ahuman concurrently treated with methotrexate or other non-biologic DMARD(such as leflunomide) or non-steroidal anti-inflammatory drug (NSAID)and/or steroid comprising the step of administering to the human aneutralizing antibody which binds human IL-17A and human IL-17F. Invarious aspects, the antibody specifically binds an epitope of humanIL-17F, the epitope comprising one or more residues selected from ARG47,ARG73, LEU75 and ILE86 of SEQ ID NO: 27. Alternatively or in addition,the antibody specifically binds an epitope of human IL-17A, the epitopecomprising one or more residues selected from TYR44, ASN45, ARG46,TRP51, ASN52, HIS54 and ASP84 of SEQ ID NO: 28. Optionally, the antibodybinds to the same epitope on human IL-17A, human IL-17F, or IL-17 A/Fheterodimer as a neutralising antibody that has a heavy chain comprisingthe sequence given in SEQ ID NO: 11 and a light chain comprising thesequence given in SEQ ID NO: 10. In various aspects, the antibodycross-blocks a neutralising antibody that has a heavy chain comprisingthe sequence given in SEQ ID NO: 11 and a light chain comprising thesequence given in SEQ ID NO: 10 and binds human IL-17A and human IL-17F.In various aspects, the antibody comprises a light chain variable domainand a heavy chain variable domain, wherein the variable domain of thelight chain comprises the sequence given in SEQ ID NO:10. In a preferredaspect, the antibody is bimekizumab. The antibody may be administered asa pharmaceutical composition. The antibody is optionally administeredsubcutaneously or intravenously.

The invention includes a method of treating rheumatoid arthritis in ahuman comprising the step of administering to the human atherapeutically effective amount of a neutralizing antibody which bindshuman IL-17A and human IL-17F. In various aspects, the antibodyspecifically binds an epitope of human IL-17F, the epitope comprisingone or more residues selected from ARG47, ARG73, LEU75 and ILE86 of SEQID NO: 27. Alternatively or in addition, the antibody specifically bindsan epitope of human IL-17A, the epitope comprising one or more residuesselected from TYR44, ASN45, ARG46, TRP51, ASN52, HIS54 and ASP84 of SEQID NO: 28. In various aspects, the antibody binds to the same epitope onhuman IL-17A, human IL-17F, or IL-17 A/F heterodimer as a neutralisingantibody that has a heavy chain comprising the sequence given in SEQ IDNO: 11 and a light chain comprising the sequence given in SEQ ID NO: 10.In various aspects, the antibody cross-blocks a neutralising antibodythat has a heavy chain comprising the sequence given in SEQ ID NO: 11and a light chain comprising the sequence given in SEQ ID NO: 10 andbinds human IL-1 7A and human IL-1 7F. Optionally, the antibodycomprises a light chain variable domain and a heavy chain variabledomain, wherein the variable domain of the light chain comprises thesequence given in SEQ ID NO:10. In a preferred aspect, the antibody isbimekizumab. The antibody may be administered as a pharmaceuticalcomposition. The antibody is optionally administered subcutaneously orintravenously.

The invention further includes a method of treating rheumatoid arthritisin a human patient comprising the step of administering to the patient aneutralizing antibody which binds human IL-17A and human IL-17F in anamount that is effective to provide an ACR20 response at week 8 or week12, an ACR50 response at week 8 or week 12, or an ACR70 response at week8 or week 12 in a population of patients in need of treatment. Forexample, in various aspects, the amount administered is effective toprovide an ACR50 response at week 8 or week 12, or an ACR70 response atweek 8 or week 12 in the population of patients. In a preferred aspect,the amount is effective to provide an ACR70 response at week 8 or week12 in a population of patients in need of treatment. In various aspects,the antibody specifically binds an epitope of human IL-17F, the epitopecomprising one or more residues selected from ARG47, ARG73, LEU75 andILE86 of SEQ ID NO: 27. Alternatively or in addition, the antibodyspecifically binds an epitope of human IL-17A, the epitope comprisingone or more residues selected from TYR44, ASN45, ARG46, TRP51, ASN52,HIS54 and ASP84 of SEQ ID NO: 28. In various embodiments, the antibodybinds to the same epitope on human IL-17A, human IL-17F, or IL-17 A/Fheterodimer as a neutralising antibody that has a heavy chain comprisingthe sequence given in SEQ ID NO: 11 and a light chain comprising thesequence given in SEQ ID NO: 10. In various embodiments, the antibodycross-blocks a neutralising antibody that has a heavy chain comprisingthe sequence given in SEQ ID NO: 11 and a light chain comprising thesequence given in SEQ ID NO: 10 and binds human IL-1 7A and human IL-17F. Optionally, the antibody comprises a light chain variable domain anda heavy chain variable domain, wherein the variable domain of the lightchain comprises the sequence given in SEQ ID NO:10. In a preferredaspect of the invention, the antibody is bimekizumab. The antibody maybe administered as a pharmaceutical composition. The antibody isoptionally administered subcutaneously or intravenously.

The invention also provides a method of treating rheumatoid arthritis ina human, comprising the step of administering to the human a loadingdose of a neutralizing antibody which binds human IL-17A and humanIL-17F followed by at least one maintenance dose of the antibody. Invarious aspects, the loading dose is between 80 and 560 mg and the atleast one maintenance dose is between 40 and 320 mg. For example, invarious embodiments, the loading dose is 80 mg and the at least onemaintenance dose is 40 mg, the loading dose is 160 mg and the at leastone maintenance dose is 80 mg, the loading dose is 240 mg and the atleast one maintenance dose is 160 mg, the loading dose is 320 mg and theat least one maintenance dose is 160 mg, or the loading dose is 560 mgand the at least one maintenance dose is 320 mg. Optionally, the loadingdose is administered followed by two maintenance doses. Also optionally,the loading dose is administered followed by at least one maintenancedose at a three week interval or a four week interval. In variousembodiments, the antibody specifically binds an epitope of human IL-17F,the epitope comprising one or more residues selected from ARG47, ARG73,LEU75 and ILE86 of SEQ ID NO: 27. Alternatively or in addition, theantibody specifically binds an epitope of human IL-17A, the epitopecomprising one or more residues selected from TYR44, ASN45, ARG46,TRP51, ASN52, HIS54 and ASP84 of SEQ ID NO: 28. In various aspects, theantibody binds to the same epitope on human IL-17A, human IL-17F, orIL-17 A/F heterodimer as a neutralising antibody that has a heavy chaincomprising the sequence given in SEQ ID NO: 11 and a light chaincomprising the sequence given in SEQ ID NO: 10. In various aspects, theantibody cross-blocks a neutralising antibody that has a heavy chaincomprising the sequence given in SEQ ID NO: 11 and a light chaincomprising the sequence given in SEQ ID NO: 10 and binds human IL-1 7Aand human IL-1 7F. Optionally, the antibody comprises a light chainvariable domain and a heavy chain variable domain, wherein the variabledomain of the light chain comprises the sequence given in SEQ ID NO:10.In a preferred aspect, the antibody is bimekizumab. The antibody may beadministered as a pharmaceutical composition. The antibody is optionallyadministered subcutaneously or intravenously.

The invention further provides a method of treating rheumatoid arthritisin a human, comprising the step of administering to the human at leastone dose of a neutralizing antibody which binds human IL-17A and humanIL-17F. Optionally, the at least one dose is between 40 and 640 mg ofthe antibody. For example, at least one dose is 40 mg of the antibody or80 mg of the antibody or 160 mg of the antibody or 240 mg of theantibody or 320 mg of the antibody or 480 mg of the antibody or 560 mgof the antibody or 640 mg of the antibody. Also optionally, the dosesare administered at a three week interval or a four week interval. Invarious aspects, the antibody specifically binds an epitope of humanIL-17F, the epitope comprising one or more residues selected from ARG47,ARG73, LEU75 and ILE86 of SEQ ID NO: 27. Alternatively or in addition,the antibody specifically binds an epitope of human IL-17A, the epitopecomprising one or more residues selected from TYR44, ASN45, ARG46,TRP51, ASN52, HIS54 and ASP84 of SEQ ID NO: 28. In various aspects, theantibody binds to the same epitope on human IL-17A, human IL-17F, orIL-17 A/F heterodimer as a neutralising antibody that has a heavy chaincomprising the sequence given in SEQ ID NO: 11 and a light chaincomprising the sequence given in SEQ ID NO: 10. In various aspects, theantibody cross-blocks a neutralising antibody that has a heavy chaincomprising the sequence given in SEQ ID NO: 11 and a light chaincomprising the sequence given in SEQ ID NO: 10 and binds human IL-1 7Aand human IL-1 7F. Optionally, the antibody comprises a light chainvariable domain and a heavy chain variable domain, wherein the variabledomain of the light chain comprises the sequence given in SEQ ID NO:10.In a preferred aspect, the antibody is bimekizumab. The antibody may beadministered as a pharmaceutical composition. The antibody is optionallyadministered subcutaneously or intravenously.

The invention also provides a method of treating axial spondyloarthritis(e.g., ankylosing spondylosis) comprising the step of administering tothe human a neutralizing antibody which binds human IL-17A and humanIL-17F. Axial spondyloarthritis refers to a group of inflammatoryarthritis diseases which primarily affects the spine and other joints,causing inflammation and chronic pain in the spine and sacroliliacjoints which may eventually result in syndemophyte formation and whichincludes both ankylosing spondylitis and nonradiographic spondylitis.Thus, the invention provides a method for treating (e.g., amelioratingthe symptoms of, reducing the progression of) ankylosing spondylosisand/or nonradiographic axial spondyloarthritis (nr-axSpA). In variousaspects, the antibody specifically binds an epitope of human IL-17F, theepitope comprising one or more residues selected from ARG47, ARG73,LEU75 and ILE86 of SEQ ID NO: 27. Alternatively or in addition, theantibody specifically binds an epitope of human IL-17A, the epitopecomprising one or more residues selected from TYR44, ASN45, ARG46,TRP51, ASN52, HIS54 and ASP84 of SEQ ID NO: 28. In various aspects, theantibody binds to the same epitope on human IL-17A, human IL-17F, orIL-17 A/F heterodimer as a neutralising antibody that has a heavy chaincomprising the sequence given in SEQ ID NO: 11 and a light chaincomprising the sequence given in SEQ ID NO: 10. In various aspects, theantibody cross-blocks a neutralising antibody that has a heavy chaincomprising the sequence given in SEQ ID NO: 11 and a light chaincomprising the sequence given in SEQ ID NO: 10 and binds human IL-1 7Aand human IL-1 7F. Optionally, the antibody comprises a light chainvariable domain and a heavy chain variable domain, wherein the variabledomain of the light chain comprises the sequence given in SEQ ID NO:10.In a preferred aspect, the antibody is bimekizumab. The antibody may beadministered as a pharmaceutical composition. The antibody is optionallyadministered subcutaneously or intravenously. Preferably the antibody isadministered in a therapeutically effective amount. Any of the dosingregimens described herein are suitable for use in the context of thismethod. For example, in various embodiments, the method comprisesadministering to a subject a 16 mg, 64 mg, 160 mg, or 320 mg of antibodyevery four weeks, optionally for a treatment period of 12 weeks, 36weeks, 48 weeks, or 52 weeks. The amount and timing of administration ispreferably sufficient to achieve at least an ASAS20 response (e.g.,ASAS40,) at week 2, week 4, week 8, or week 12 of treatment. ASASscoring and methods of evaluating the severity of axial spondylitis arefurther described in Ann Rheum Dis 2009; 68; ii1-ii44. In one examplethe amount and timing of administration is preferably sufficient toachieve an ASAS40 at week 12 of treatment. In one example the amount andtiming of administration is preferably sufficient to provide at least30% or at least 40% or at least 45% or at least 50% of subjectsachieving an ASAS40 response at week 12 of treatment. In variousembodiments, the invention provides a method of inhibiting (e.g.,slowing the progression of) periosteal bone formation in a human, suchas a human suffering from spondyloarthritis (e.g., ankylosingspondylosis), by administering a neutralizing antibody which binds humanIL-17A and human IL-17F as described herein. Periosteal bone formationis evaluated via, e.g., radiography

In any of the embodiments of the method of treating axialspondyloarthitis including ankylosing spondylitis and nr-axSpA in ahuman comprising the step of administering to the human a neutralizingantibody which binds human IL-17A and human IL-17F, the human optionallyhas a diagnosis of adult-onset ankylosing spondylitis or nr-axSpA.Optionally, the human is at least 18 years of age and/or was diagnosedat least six months prior to administration of the antibody.

Also optionally, the human has been classified based on the modified NewYork or ASAS criteria. In any of the embodiments described above, thehuman has active axial arthritis.

In any of the embodiments of the method of treating axialspondyloarthritis including ankylosing spondylitis and/or nr-axSpA in ahuman comprising the step of administering to the human a neutralizingantibody which binds human IL-17A and human IL-17F described herein, thehuman optionally is an inadequate responder to at least one nonsteroidalanti-inflammatory drug (“NSAID”) and/or one or more approved biologicDMARD (e.g., a TNF inhibitor such as an anti-TNF antibody, examplesincluding inflixumab or adalimumab, or a soluble TNF receptor, such asetanercept).

The invention also provides a method of treating axial spondyloarthritisincluding ankylosing spondylitis and/or nr-axSpA in a human concurrentlytreated with a non-steroidal anti-inflammatory drug (NSAID) comprisingthe step of administering to the human a neutralizing antibody whichbinds human IL-17A and human IL-17F.

Also included in the invention is a method of treating psoriaticarthritis comprising the step of administering a neutralizing antibodywhich binds human IL-17A and human IL-17F in an amount that is effectiveto provide at least 50% of subjects achieving an ACR20 response at week8 or week 12. For example, the amount is effective to provide at least51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64 or 65% ofsubjects achieving an ACR20 response at week 8 or week 12. In oneexample, the amount is effective to provide at least 50-90% or 60-90% or63-91% of subjects achieving an ACR20 response at week 8 or week 12. Inone example, the amount is effective to provide at least 40%, at least45%, at least 50% or at least 55% of subjects achieving an ACR50response at week 8 or week 12 or week 20. Alternatively or in addition,the amount of neutralizing antibody is effective to provide at least 80%of subjects achieving a PASI75 response at week 8 or week 12. Forexample, the amount is effective to provide 80-100% of subjectsachieving a PASI75 response at week 8 or week 12, such as an amounteffective to provide at least 80, 85, 90, 95 or 99% of subjectsachieving a PASI75 response at week 8 or week 12. In variousembodiments, the amount of neutralizing antibody is effective to provideat least 60% of subjects achieving a PASI90 response or a PASI100response at week 8 or week 12, e.g., an amount effective to provide60-100% or 62-96% of subjects achieving a PASI90 response at week 8 orweek 12 (such as an amount effective to provide at least 60, 65, 70, 75,80, 85, 90, 95 or 96% of subjects achieving a PASI90 response at week 8or week 12).

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 : Nucleotide and Amino Acid Sequences

FIG. 2 : CASPAR criteria

FIG. 3 a : PASI 50/75/90 response at week 8 for cohorts 1-4 described inExample 1.

FIG. 3 b : Time course of PASI 90-response (PA0007) from first dose(day0) to day 140 (week 20) in Example 1.

FIG. 4 : Secukinumab Future 1 Results: PASI

FIG. 5 a : ACR20/50/70 response at week 8 for cohorts 1-4 described inExample 1.

FIGS. 5(b)-5(d): Summary Plots of the ACR20/50/70 response rates fromPA0007 from start of study (day 0) to day 140 (week 20) (Example 1).

FIG. 6 : Secukinumab Future 1 Results and Cimzia RAPID PSA results:ACR20

FIG. 7 : Summary Table of Bayesian Analysis

FIG. 8 : Summary Table of ACR20 response at week 8 in psoriaticarthritis for registered anti-TNFs or Phase III results. References 1.Mease P J, Gladman D D, Ritchlin C T, Ruderman E M, Steinfeld S D, ChoyE H, et al. Adalimumab for the treatment of patients with moderately toseverely active psoriatic arthritis: results of a double-blind,randomized, placebo-controlled trial. Arthritis and rheumatism. 2005;52(10):3279-89. 2. Kavanaugh A, McInnes I, Mease P, Krueger G G, GladmanD, Gomez-Reino J, et al. Golimumab, a new human tumor necrosis factoralpha antibody, administered every four weeks as a subcutaneousinjection in psoriatic arthritis: Twenty-four-week efficacy and safetyresults of a randomized, placebo-controlled study. Arthritis andrheumatism. 2009; 60(4):976-86. 3. Mease P J, Fleischmann R, Deodhar AA, Wollenhaupt J, Khraishi M, Kielar D, et al. Effect of certolizumabpegol on signs and symptoms in patients with psoriatic arthritis:24-week results of a Phase 3 double-blind randomised placebo-controlledstudy (RAPID-PsA). Annals of the rheumatic diseases. 2014; 73(1):48-55.4. McInnes I B, Mease P J, Kirkham B, Kavanaugh A, Ritchlin C T, RahmanP, et al. Secukinumab, a human anti-interleukin-17A monoclonal antibody,in patients with psoriatic arthritis (FUTURE 2): a randomised,double-blind, placebo-controlled, phase 3 trial. Lancet. 2015;386(9999):1137-46. 5. McInnes I B, Kavanaugh A, Gottlieb A B, Puig L,Rahman P, Ritchlin C, et al. Efficacy and safety of ustekinumab inpatients with active psoriatic arthritis: 1 year results of the phase 3,multicentre, double-blind, placebo-controlled PSUMMIT 1 trial. Lancet.2013; 382(9894):780-9.

FIG. 9 : Targeted CA028_0496.g3 PK concentrations

FIG. 10 : Summary PK plot of predicted SC dosing, illustrating that adose of 320 loading followed by 160 mg Q4W or 160 mg Q4W and higher, areable to achieve the plasma concentrations studied in PA0007 at the top 3doses.

FIG. 11 : Percent change from baseline in lesional severity score instudy UP0008

FIG. 12 : Percent Change for baseline in PASI in study UP0008

FIG. 13 : Summary Table of PASI 90 response in study UP0008

FIGS. 14A-14C: Mean percentage change from baseline in (A) LSS, (B) PASIand (C) PGA in the placebo and bimekizumab cohorts. Closedcircles=placebo; diamonds=8 mg bimekizumab; closed squares=40 mgbimekizumab; open squares=160 mg bimekizumab; open diamonds=480 mgbimekizumab; open triangles=640 mg bimekizumab.

FIGS. 15A-15G: FIGS. 15A-15E are bar graphs illustrating osteogenic geneexpression in hPDSCs following treatment with GFC (growth factorcocktail; first bar from left), GFC (-IL-6) (growth factor cocktailwithout IL-6; second bar), TH-17SN (TH-17 supernatant in (GFC-IL-6),third bar), TH-17SN+IL-17A mAb ((TH-17 supernatant in (GFC-IL-6) withIL-17A monoclonal antibody treatment; fourth bar), or IL-17F mAb ((TH-17supernatant in (GFC-IL-6) with IL-17F monoclonal antibody treatment;fifth bar), or IL-17A/F mAb ((TH-17 supernatant in (GFC-IL-6) withIL-17A/F monoclonal antibody treatment; sixth bar). FIG. 15F is a bargraph illustrating in vitro mineralisation (y-axis=Absorbance at 595 nm;bars from left to right: Control, GFC, GFC-IL-6, TH-17SN, IL-17A mAb,IL-17F mAb, IL-17A/F mAb). FIG. 15G is a bar graph illustrating IL-6gene expression following treatment with GFC (growth factor cocktail;first bar from left), GFC (-IL-6) (growth factor cocktail without IL-6;second bar), TH-17SN (TH-17 supernatant in (GFC-IL-6), third bar),TH-17SN+IL-17A mAb ((TH-17 supernatant in (GFC-IL-6) with IL-17Amonoclonal antibody treatment; fourth bar), or IL-17F mAb ((TH-17supernatant in (GFC-IL-6) with IL-17F monoclonal antibody treatment;fifth bar), or IL-17A/F mAb ((TH-17 supernatant in (GFC-IL-6) withIL-17A/F monoclonal antibody treatment; sixth bar). Results areexpressed as the mean fold change in expression compared to GM±SEM.***p<0.001; **p<0.01; *p<0.05 as compared by one-way ANOVA (n=3) betweenall treatment groups.

FIGS. 16A-16B: Bar graphs illustrating reduction in expression of IL-6(FIG. 16A) and RUNX2 (FIG. 16B) in three patient samples (SRSC04,SRSCO6, and SRSCO7). hPDSCs treated with 10% AS patient serum (CTRL,first bar from left), or AS patient sera with IgG mAb control (secondbar), IL-17A mAb (third bar), IL-17F mAb (fourth bar), IL-17A/F mAb(fifth bar) preincubation. Results are expressed as the mean relativeexpression ±SEM. (***p<0.001; **p<0.01; *p<0.05) § § § p<0.01(comparisons between neutralisation groups as compared by one-way ANOVA(n=3) in all cases).

DETAILED DESCRIPTION OF THE INVENTION Antibodies

In one embodiment, the antibodies of the invention specifically bind toIL-17A. Specifically binding means that the antibodies have a greateraffinity for IL-17A polypeptides than for other polypeptides.

In one embodiment, the antibodies of the invention specifically bind toIL-17F. Specifically binding means that the antibodies have a greateraffinity for IL-17F polypeptides than for other polypeptides.

In a preferred embodiment, the antibodies of the invention specificallybind to IL-17A and IL-17F. Specifically binding means that theantibodies have a greater affinity for IL-17A and IL-17F polypeptides(including the IL-17A/IL-17F heterodimer) than for other polypeptides.

Preferably, the IL-17A and IL-17F polypeptides are human. In oneembodiment, the antibody also binds cynomolgus IL-17A and/or IL-17F.

It will be appreciated that an antibody of the invention thatneutralizes both IL-17A and IL-17F may be generated as a cross-reactiveantibody as described herein below or by combining both an IL-17Abinding domain with an IL-17F binding domain in a bispecific antibody.

In one embodiment, an antibody of the invention which is capable ofbinding to both IL-17A and IL-17F is capable of neutralising theactivity of both isoforms of IL-17. Preferably, an antibody of theinvention neutralises the activity of both IL-17A and IL-17F. In oneembodiment, an antibody of the invention also neutralises the activityof the IL-17A/IL-17F heterodimer. The antibodies provided by this aspectof the invention therefore have the advantageous property that they caninhibit the biological activity of both IL-17A and IL-17F. Accordingly,the invention also provides the use of such antibodies in the treatmentof and/or prophylaxis of a disease mediated by either or both of IL-17Aor IL-17F such as autoimmune or inflammatory disease.

As used herein, the term “neutralising antibody” describes an antibodythat is capable of neutralising the biological signalling activity ofIL-17A and/or IL17F and/or IL-17A/F heterodimer, for example by blockingbinding of IL-17A and/or IL17F to one or more of their receptors and byblocking binding of the IL-17A/IL-17F heterodimer to one or more of itsreceptors. It will be appreciated that the term “neutralizing” as usedherein refers to a reduction in biological signalling activity which maybe partial or complete. Further, it will be appreciated that the extentof neutralisation of IL-17A and IL-17F activity by an antibody whichbinds both IL-17A and IL-17F may be the same or different. In oneembodiment, the extent of neutralisation of the activity of theIL-17A/IL-17F heterodimer may be the same or different as the extent ofneutralisation of IL-17A or IL-17F activity.

IL-17A or IL-17F polypeptides, or a mixture of the two, or cellsexpressing one or both of said polypeptides, can be used to produceantibodies which specifically recognise one or both polypeptides. TheIL-17 polypeptides (IL-17A and IL-17F) may be “mature” polypeptides orbiologically active fragments or derivatives thereof which preferablyinclude the receptor binding site. Preferably the IL-17 polypeptides arethe mature polypeptides provided in SEQ ID NOs: 27 and 28 for IL-17A andIL-17F respectively. IL-17 polypeptides may be prepared by processeswell known in the art from genetically engineered host cells comprisingexpression systems or they may be recovered from natural biologicalsources.

In the application, the term “polypeptides” includes peptides,polypeptides and proteins. These are used interchangeably unlessotherwise specified.

The IL-17 polypeptide may in some instances be part of a larger proteinsuch as a fusion protein for example fused to an affinity tag.Antibodies generated against these polypeptides may be obtained, whereimmunisation of an animal is necessary, by administering thepolypeptides to an animal, preferably a non-human animal, usingwell-known and routine protocols, see for example Handbook ofExperimental Immunology, D. M. Weir (ed.), Vol 4, Blackwell ScientificPublishers, Oxford, England, 1986). Many warm-blooded animals, such asrabbits, mice, rats, sheep, cows or pigs may be immunized. Mice,rabbits, pigs and rats may be preferred.

Antibodies for use in the invention include whole antibodies andfunctionally active fragments or derivatives thereof and may be, but arenot limited to, monoclonal, multi-valent, multi-specific, bispecific,fully human, humanized or chimeric antibodies, domain antibodies e.g.VH, VL, VHH, single chain antibodies, Fab fragments, Fab′ and F(ab′)₂fragments and epitope-binding fragments of any of the above. Otherantibody fragments include those described in International patentapplications WO2005003169, WO2005003170, WO2005003171, WO2009040562 andWO2010035012. Antibody fragments and methods of producing them are wellknown in the art, see for example Verma et al., 1998, Journal ofImmunological Methods, 216, 165-181; Adair and Lawson, 2005. Therapeuticantibodies. Drug Design Reviews—Online 2(3):209-217.

Antibodies for use in the invention include immunoglobulin molecules andimmunologically active portions of immunoglobulin molecules, i.e.,molecules that contain an antigen binding site that specifically bindsan antigen. The immunoglobulin molecules of the invention can be of anyclass (e.g. IgG, IgE, IgM, IgD and IgA) or subclass of immunoglobulinmolecule.

Monoclonal antibodies may be prepared by any method known in the artsuch as the hybridoma technique (Kohler & Milstein, 1975, Nature,256:495-497), the trioma technique, the human B-cell hybridoma technique(Kozbor et al., 1983, Immunology Today, 4:72) and the EBV-hybridomatechnique (Cole et al., Monoclonal Antibodies and Cancer Therapy, pp77-96, Alan R Liss, Inc., 1985).

Antibodies for use in the invention may also be generated using singlelymphocyte antibody methods by cloning and expressing immunoglobulinvariable region cDNAs generated from single lymphocytes selected for theproduction of specific antibodies by for example the methods describedby Babcook, J. et al., 1996, Proc. Natl. Acad. Sci. USA93(15):7843-78481; WO92/02551; WO2004/051268 and International PatentApplication number WO2004/106377.

Humanized antibodies are antibody molecules from non-human specieshaving one or more complementarity determining regions (CDRs) from thenon-human species and a framework region from a human immunoglobulinmolecule (see, e.g. U.S. Pat. No. 5,585,089; WO91/09967).

Chimeric antibodies are those antibodies encoded by immunoglobulin genesthat have been genetically engineered so that the light and heavy chaingenes are composed of immunoglobulin gene segments belonging todifferent species. These chimeric antibodies are likely to be lessantigenic. Bivalent antibodies may be made by methods known in the art(Milstein et al., 1983, Nature 305:537-539; WO 93/08829, Traunecker etal., 1991, EMBO J. 10:3655-3659). Multi-valent antibodies may comprisemultiple specificities or may be monospecific (see for example WO92/22853 and WO05/113605).

In one embodiment, the antibody provided by the invention is amonoclonal antibody. In one embodiment, the antibody provided by theinvention is a humanized antibody. In one embodiment, the antibodyprovided by the invention is a chimeric antibody. The antibody moleculesof the invention preferably comprise a complementary light chain or acomplementary heavy chain, respectively.

The antibodies for use in the invention can also be generated usingvarious phage display methods known in the art and include thosedisclosed by Brinkman et al. (in J. Immunol. Methods, 1995, 182: 41-50),Ames et al. (J. Immunol. Methods, 1995, 184:177-186), Kettleborough etal. (Eur. J. Immunol. 1994, 24:952-958), Persic et al. (Gene, 1997 1879-18), Burton et al. (Advances in Immunology, 1994, 57:191-280) and WO90/02809; WO 91/10737; WO 92/01047; WO 92/18619; WO 93/11236; WO95/15982; WO 95/20401; and U.S. Pat. Nos. 5,698,426; 5,223,409;5,403,484; 5,580,717; 5,427,908; 5,750,753; 5,821,047; 5,571,698;5,427,908; 5,516,637; 5,780,225; 5,658,727; 5,733,743 and 5,969,108.Techniques for the production of single chain antibodies, such as thosedescribed in U.S. Pat. No. 4,946,778 can also be adapted to producesingle chain antibodies which bind to IL-17A and IL-17F. Also,transgenic mice, or other organisms, including other mammals, may beused to express humanized antibodies, including those within the scopeof the invention.

In one embodiment, the antibody provided by the invention is aCDR-grafted antibody molecule. As used herein, the term ‘CDR-graftedantibody molecule’ refers to an antibody molecule wherein the heavyand/or light chain contains one or more CDRs (including, if desired, oneor more modified CDRs) from a donor antibody (e.g. a murine monoclonalantibody) grafted into a heavy and/or light chain variable regionframework of an acceptor antibody (e.g. a human antibody). For a review,see Vaughan et al, Nature Biotechnology, 16, 535-539, 1998. In oneembodiment, rather than the entire CDR being transferred, only one ormore of the specificity determining residues from any one of the CDRsdescribed herein above are transferred to the human antibody framework(see, for example, Kashmiri et al., 2005, Methods, 36, 25-34). In oneembodiment, only the specificity determining residues from one or moreof the CDRs described herein above are transferred to the human antibodyframework. In another embodiment, only the specificity determiningresidues from each of the CDRs described herein above are transferred tothe human antibody framework.

When the CDRs or specificity determining residues are grafted, anyappropriate acceptor variable region framework sequence may be usedhaving regard to the class/type of the donor antibody from which theCDRs are derived, including mouse, primate and human framework regions.Preferably, the CDR-grafted antibody according to the invention has avariable domain comprising human acceptor framework regions as well asone or more of the CDRs or specificity determining residues describedabove. Thus, provided in one embodiment is a neutralising CDR-graftedantibody wherein the variable domain comprises human acceptor frameworkregions and non-human donor CDRs.

Examples of human frameworks which can be used in the invention are KOL,NEWM, REI, EU, TUR, TEI, LAY and POM (Kabat et al., supra). For example,KOL and NEWM can be used for the heavy chain, REI can be used for thelight chain and EU, LAY and POM can be used for both the heavy chain andthe light chain. Alternatively, human germline sequences may be used;these are available at, for example: http://vbase.mrc-cpe.cam.ac.uk/. Ina CDR-grafted antibody of the invention, the acceptor heavy and lightchains do not necessarily need to be derived from the same antibody andmay, if desired, comprise composite chains having framework regionsderived from different chains.

As described herein above, the antibody molecule of the invention maycomprise a complete antibody molecule having full length heavy and lightchains or a fragment thereof, such as a domain antibody e.g. VH, VL,VHH, Fab, modified Fab, Fab′, F(ab′)₂, Fv or scFv fragment.

It will be appreciated that the antibodies of the invention, inparticular the antibody fragments described above, may be incorporatedinto other antibody formats, in particular, multi-specific antibodies,such as bi or tri specific antibodies, where specificity is provided byan antibody of the invention, i.e., specificity for IL-17A and IL-17F(including IL-17A/F heterodimer). Accordingly, in one embodiment, theinvention provides a multi-specific antibody comprising one or more ofthe antibody fragments described herein above. Such multi-specificantibodies may comprise one or more further antibody fragments withbinding specificity for another antigen, such as serum albumin, such ashuman serum albumin in order to extend the half life of themulti-specific antibody. For example, antibody fragments described inWO2012/156219 and combinations or variants thereof which comprise bothan anti-IL-17A/F VHH binding domain and a serum albumin VHH bindingdomain.

Examples of multi-specific antibodies include bi, tri or tetra-valentantibodies, Bis-scFv, diabodies, triabodies, tetrabodies, bibodies andtribodies (see for example Holliger and Hudson, 2005, Nature Biotech23(9): 1126-1136; Schoonjans et al. 2001, Biomolecular Engineering, 17(6), 193-202). Other multi-specific antibodies include Fab-Fv, Fab-dsFv,Fab-Fv-Fv. Fab-Fv-Fc and Fab-dsFv-PEG fragments described inWO2009040562, WO2010035012, WO2011/08609, WO2011/030107 andWO2011/061492 respectively.

The constant region domains of the antibody molecule of the invention,if present, may be selected having regard to the proposed function ofthe antibody molecule, and in particular the effector functions whichmay be required. For example, the constant region domains may be humanIgA, IgD, IgE, IgG or IgM domains. In particular, human IgG constantregion domains may be used, especially of the IgG1 and IgG3 isotypeswhen the antibody molecule is intended for therapeutic uses and antibodyeffector functions are required. Alternatively, IgG2 and IgG4 isotypesmay be used when the antibody molecule is intended for therapeuticpurposes and antibody effector functions are not required, e.g. forsimply blocking IL-17 activity. For example IgG4 molecules in which theserine at position 241 has been changed to proline as described in Angalet al., Molecular Immunology, 1993, 30 (1), 105-108 may be used.Particularly preferred is the IgG4 constant domain that comprises thischange.

It will also be understood by one skilled in the art that antibodies mayundergo a variety of posttranslational modifications. The type andextent of these modifications often depends on the host cell line usedto express the antibody as well as the culture conditions. Suchmodifications may include variations in glycosylation, methionineoxidation, diketopiperazine formation, aspartate isomerization andasparagine deamidation. A frequent modification is the loss of acarboxy-terminal basic residue (such as lysine or arginine) due to theaction of carboxypeptidases (as described in Harris, R J. Journal ofChromatography 705:129-134, 1995). Accordingly, the C-terminal lysine ofthe antibody heavy chain, for example as given in FIG. 1 SEQ ID NO: 16,may be absent.

In one embodiment, the antibody heavy chain comprises a CH1 domain andthe antibody light chain comprises a CL domain, either kappa or lambda.

Fully human antibodies are those antibodies in which the variableregions and the constant regions (where present) of both the heavy andthe light chains are all of human origin, or substantially identical tosequences of human origin, not necessarily from the same antibody.Examples of fully human antibodies may include antibodies produced forexample by the phage display methods described above and antibodiesproduced by mice in which the murine immunoglobulin variable andconstant region genes have been replaced by their human counterparts,e.g., as described in general terms in EP0546073 B1, U.S. Pat. Nos.5,545,806, 5,569,825, 5,625,126, 5,633,425, 5,661,016, 5,770,429, EP0438474 B1 and EP0463151 B1.

The above antibodies are described for purposes of reference and exampleonly and do not limit the scope of invention.

Inhibitors of IL-17A and IL-17F activity are known in the art, forexample those described herein. Antibodies which bind both IL-17A andIL-17F have been described in WO2007/106769, WO2008/047134,WO2009/136286, WO2010/025400, and WO2012/156219. IL-17A and IL-17Factivity can also be antagonized through use of an anti-IL-17RC antibodyor an IL-17RC fusion protein, as described in US2007196371A.

U.S. Pat. No. 8,303,953 (Oct. 18, 2006 priority date) describes a highaffinity antibody, CA028_00496 which binds human IL-17A, IL-17F andIL-17A/F heterodimer, the sequence of which is provided herein in Figure[1]. CA028_0496 is a humanised neutralising antibody which comprises thegrafted variable regions gL7 and gH9, the sequences of which areprovided in U.S. Pat. No. 8,303,953 (priority date 18 Oct. 2006) andherein in Figure [1]. The heavy chain acceptor framework is the humangermline sequence VH3 1-3 3-07 with framework 4 coming from this portionof the human JH-region germline JH4. The light chain acceptor frameworkis the human germline sequence VK1 2-1-(1) L4, with framework 4 comingfrom this portion of the human JK-region germline JKL. Examples 2-4 ofU.S. Pat. No. 8,303,953, as well as the DNA Manipulations and GeneralMethods section therein, describe characterization and testing of theneutralizing activity and affinity of CA028_0496.

U.S. Pat. No. 8,580,265 (Jan. 14, 2011 priority date) describes asecond, higher affinity antibody, CA028_00496.g3, also known as UCB4940or Bimekizumab, which binds human IL-17A, IL-17F and IL-17A/Fheterodimer, the sequence of which is provided herein in Figure [1]. Asdescribed in U.S. Pat. No. 8,580,265, antibody CA028_0496 was affinitymatured to improve the affinity of the antibody for IL-17F whileretaining affinity for IL-17A. This affinity matured antibody,CA028_0496.g3 (also known as UCB4940 or bimekizumab), was expressed asan IgG1. The final sequence of the affinity matured variable regions ofCA028_0496.g3 is given in FIGS. 1 a and 1 b of U.S. Pat. No. 8,580,265,and herein in Figure [1]. U.S. Pat. No. 8,679,494 (Apr. 23, 2008priority date) provides novel neutralising epitopes on IL-17A and IL-17Fand antibodies which bind to, and/or interact with, those epitopes, thesequences of which are provided herein in Figure [1]. The aforementionedpatents are incorporated by reference as if fully set forth herein.

In antibody CA028_0496.g3, the heavy chain variable region sequence isthe same as that of the parent antibody CA028_0496. In contrast, thelight chain variable region differs by 5 amino acids. The five residuesthat differ between the light chain of antibody CA028_0496 and antibodyCA028_0496.g3 are underlined in FIG. 1 a of U.S. Pat. No. 8,580,265.Three residues were in the CDRs and two in the framework. Accordingly inone embodiment, the light chain variable domain comprises an arginineresidue at position 30, a serine residue at position 54, an isoleucineresidue at position 56, an aspartic acid residue at position 60 and anarginine residue at position 72.

Antibody CA028_0496.g3 selectively and potently inhibits the activity ofboth IL-17A and IL-17F isoforms in-vitro. Antibody CA028_0496.g3 bindsto IL-17A, IL-17F and the IL-17A/F heterodimer and neutralizes thebioactivity of each cytokine by blocking the cytokines from signallingthrough the IL-17RA/RC complex.

Characterization of CA028_0496.g3 and CA028_0496 and their properties isdescribed in Examples 2 and 3 of U.S. Pat. No. 8,580,265 as if fully setforth herein. As detailed in U.S. Pat. No. 8,580,265, biomolecularanalysis of antibody CA028_0496.g3 was performed using the Biacore 3000(Biacore AB). The assay format was a capture of the antibodyCA028_0496.g3 by an immobilised anti-human IgG Fc-specific antibody,followed by the titration of recombinant human IL-17A or human IL-17Fover the captured surface. Additional detail regarding surface plasmonresonance (Biacore) assays are as follows; while the details aredescribed by referencing a particular antibody, the parameters describedherein are suitable for use in characterizing any antibody describedherein. Assays were performed at 25° C.

Affinipure F(ab′)₂ fragment goat anti-human IgG Fc specific (JacksonImmunoResearch) was immobilised on a CM5 Sensor Chip (Biacore AB) viaamine coupling chemistry to a level of approximately 6000 response units(RU). HBS-EP buffer (10 mM HEPES pH7.4, 0.15M NaCl, 3 mM EDTA, 0.005%Surfactant P20, Biacore AB) was used as the running buffer with a flowrate of 10 microL/minute (min). A 10 μL injection of CA028_00496.g3 at0.5 μg/mL was used for capture by the immobilised anti-human IgG Fc.Human IL-17A was titrated over the captured CA028_00496.g3 from 5 nM ata flow rate of 30 μL/min for 3 min followed by a 20 min dissociation.Human IL-17F (R&D systems) was titrated over the captured CA028_00496.g3from 10 nM at a flow rate of 30 μL/min for 3 min followed by a 5 mindissociation. The surface was regenerated at a flow rate of 10 μL/min bya 10 μL injection of 40 mM HCl followed by a 5 L injection of 5 mM NaOH.Double referenced background subtracted binding curves were analysedusing the BIA evaluation software (version 4.1) following standardprocedures. Kinetic parameters were determined from the fittingalgorithm.

Data are detailed in Table 1.

TABLE 1 Affinity of bimekizumab against human IL-17F and IL-17A. ka(M−1s−1) kd (s−1) KD (M) KD (pM) hIL-17F 2.49E+06 8.74E−05 3.51E−11 353.49E+06 5.08E−05 1.46E−11 15 2.99E+06 6.91E−05 2.31E−11 23 hIL-17A4.66E+06 2.04E−05 4.38E−12 4.4 4.52E+06 8.66E−06 1.92E−12 1.9 4.59E+061.45E−05 3.17E−12 3.2

As described in U.S. Pat. No. 8,580,265, the preferred framework regionfor the heavy chain of CA028_0496.g3 is derived from the human sub-groupVH3 sequence 1-3 3-07 together with JH4, as previously described inWO2008/047134. Accordingly, an embodiment of the invention may be aneutralising CDR-grafted antibody comprising at least one non-humandonor CDR wherein the heavy chain framework region is derived from thehuman subgroup sequence 1-3 3-07 together with JH4. The sequence ofhuman JH4 is as follows: (YFDY)WGQGTLVTVSS. The YFDY motif is part ofCDR-H3 and is not part of framework 4 (Ravetch, J V. et al., 1981, Cell,27, 583-591).

As described in U.S. Pat. No. 8,580,265, the preferred framework regionfor the light chain of CA028_0496.g3 is derived from the human germlinesub-group VK1 sequence 2-1-(1) L4 together with JK1, as previouslydescribed in WO2008/047134. Accordingly, an embodiment of the inventionmay be a neutralising CDR-grafted antibody comprising at least onenon-human donor CDR wherein the light chain framework region is derivedfrom the human subgroup sequence VK1 2-1-(1) L4 together with JKL. TheJK1 sequence is as follows: (WT)FGQGTKVEIK. The WT motif is part ofCDR-L3 and is not part of framework 4 (Hieter, P A., et al., 1982, J.Biol. Chem., 257, 1516-1522).

Also, in CA028_0496.g3, the framework regions need not have exactly thesame sequence as those of the acceptor antibody. For instance, unusualresidues may be changed to more frequently-occurring residues for thatacceptor chain class or type. Alternatively, selected residues in theacceptor framework regions may be changed so that they correspond to theresidue found at the same position in the donor antibody (see Reichmannet al., 1998, Nature, 332, 323-324). Such changes should be kept to theminimum necessary to recover the affinity of the donor antibody. Aprotocol for selecting residues in the acceptor framework regions whichmay need to be changed is set forth in WO 91/09967.

In one embodiment, in CA028_0496.g3, if the acceptor heavy chain has thehuman VH3 sequence 1-3 3-07 together with JH4, then the acceptorframework regions of the heavy chain comprise, in addition to one ormore donor CDRs, a donor residue at least position 94 (according toKabat et al., (supra)). Accordingly, an embodiment of the invention maybe a CDR-grafted antibody, wherein at least the residue at position 94of the variable domain of the heavy chain is a donor residue.

In one embodiment, in CA028_0496.g3, if the acceptor light chain has thehuman sub-group VK1 sequence 2-1-(1) L4 together with JK1, then no donorresidues are transferred i.e. only the CDRs are transferred.Accordingly, an embodiment of the invention may be a CDR-graftedantibody wherein only the CDRs are transferred to the donor framework.

Donor residues are residues from the donor antibody, i.e. the antibodyfrom which the CDRs were originally derived.

Antibody CA028_0496.g3 is not pharmacologically active in rodents as itdoes not bind to either IL-17A or IL-17F from rat or mouse. AntibodyCA028_0496.g3 has been shown to bind to IL-17A and IL-17F in thecynomolgus monkey and nonclinical evaluation demonstrates it to bepharmacologically active in vivo in the cynomolgus monkey. In humans,antibody CA028_0496.g3 displays a long half-life in a dose-proportionalmanner, with PK for doses between 8 mg and 640 mg ranging between 17.00days and 25.55 days (e.g., 23.6 days) across the treatment groups.

The above antibodies are described for purposes of reference and exampleonly and do not limit the scope of invention. For example, as describedherein, it will be appreciated that the affinity of antibodies providedby the invention may be altered using any suitable method known in theart. The invention therefore also relates to variants of the antibodymolecules of the invention, which have an improved affinity for IL-17Aand/or IL-17F. Such variants can be obtained by a number of affinitymaturation protocols including mutating the CDRs (Yang et al., J. Mol.Biol., 254, 392-403, 1995), chain shuffling (Marks et al.,Bio/Technology, 10, 779-783, 1992), use of mutator strains of E. coli(Low et al., J. Mol. Biol., 250, 359-368, 1996), DNA shuffling (Pattenet al., Curr. Opin. Biotechnol., 8, 724-733, 1997), phage display(Thompson et al., J. Mol. Biol., 256, 77-88, 1996) and sexual PCR(Crameri et al., Nature, 391, 288-291, 1998). Vaughan et al. (supra)discusses these methods of affinity maturation.

Screening for antibodies can be performed using assays to measurebinding to human IL-17A and human IL-17F, for example BIAcore™ assays.BIAcore™ (i.e., surface plasmon resonance assays) are described herein.Suitable neutralisation assays are known in the art, see for exampleWO2008/047134. An exemplary cell-based neutralization assay utilizesHeLa cells. For example, HeLa cells are grown in Dulbecco's modifiedEagle's medium (DMEM) supplemented with 10% foetal calf serum,penicillin, gentamycin and glutamine. 1×10⁴ cells are plated out into 96well flat bottomed tissue culture plates. Cells are incubated overnightand washed once in assay buffer. HeLa cells are stimulated with acombination of recombinant human IL-17F (125 ng/ml) or human IL-17A (25ng/ml) and tumour necrosis factor-alpha (TNF-α) (1 ng/ml) for 48 hoursin the presence of varying concentrations of candidate antibody. In theHeLa cell line, IL-17A or IL-17F synergises with TNF-alpha to induce theproduction of IL-6, which can be quantified using a specific MSD assaykit. The resulting amount of secreted IL-6 is measured using Meso ScaleDiscovery (MSD) assay technology and IC50 values calculated. Theactivity of an antibody can be expressed as the dose required to inhibit50% of the activity of IL-17A or IL-17F (IC₅₀).

“Identity”, as used herein, indicates that at any particular position inthe aligned sequences, the amino acid residue is identical between thesequences. “Similarity”, as used herein, indicates that, at anyparticular position in the aligned sequences, the amino acid residue isof a similar type between the sequences. For example, leucine may besubstituted for isoleucine or valine. Other amino acids which can oftenbe substituted for one another include but are not limited to:phenylalanine, tyrosine and tryptophan (amino acids having aromatic sidechains); lysine, arginine and histidine (amino acids having basic sidechains); aspartate and glutamate (amino acids having acidic sidechains); asparagine and glutamine (amino acids having amide sidechains); and cysteine and methionine (amino acids havingsulphur-containing side chains).

Degrees of identity and similarity can be readily calculated(Computational Molecular Biology, Lesk, A. M., ed., Oxford UniversityPress, New York, 1988; Biocomputing. Informatics and Genome Projects,Smith, D. W., ed., Academic Press, New York, 1993; Computer Analysis ofSequence Data, Part 1, Griffin, A. M., and Griffin, H. G., eds., HumanaPress, New Jersey, 1994; Sequence Analysis in Molecular Biology, vonHeinje, G., Academic Press, 1987; and Sequence Analysis Primer,Gribskov, M. and Devereux, J., eds., M Stockton Press, New York, 1991).

The residues in antibody variable domains are conventionally numberedaccording to a system devised by Kabat et al. This system is set forthin Kabat et al., 1987, in Sequences of Proteins of ImmunologicalInterest, US Department of Health and Human Services, NIH, USA(hereafter “Kabat et al. (supra)”). This numbering system is used in thepresent specification except where otherwise indicated.

The Kabat residue designations do not always correspond directly withthe linear numbering of the amino acid residues. The actual linear aminoacid sequence may contain fewer or additional amino acids than in thestrict Kabat numbering corresponding to a shortening of, or insertioninto, a structural component, whether framework or complementaritydetermining region (CDR), of the basic variable domain structure. Thecorrect Kabat numbering of residues may be determined for a givenantibody by alignment of residues of homology in the sequence of theantibody with a “standard” Kabat numbered sequence.

The CDRs of the heavy chain variable domain are located at residues31-35 (CDR-H1), residues 50-65 (CDR-H2) and residues 95-102 (CDR-H3)according to the Kabat numbering system. However, according to Chothia(Chothia, C. and Lesk, A. M. J. Mol. Biol., 196, 901-917 (1987)), theloop equivalent to CDR-H1 extends from residue 26 to residue 32. Thus‘CDR-H1’, as used herein, comprises residues 26 to 35, as described by acombination of the Kabat numbering system and Chothia's topological loopdefinition.

The CDRs of the light chain variable domain are located at residues24-34 (CDR-L1), residues 50-56 (CDR-L2) and residues 89-97 (CDR-L3)according to the Kabat numbering system.

In one embodiment, the antibody provided by the invention is aCDR-grafted antibody molecule comprising one or more of the CDRsprovided in SEQ ID NOs:1 to 8.

In one embodiment, the invention provides a neutralising antibody havingspecificity for human IL-17A and human IL-17F, comprising a heavy chain,wherein the variable domain of the heavy chain comprises the sequencegiven in SEQ ID NO:1 for CDR-H1, the sequence given in SEQ ID NO:2 forCDR-H2 and the sequence given in SEQ ID NO:3 for CDR-H3.

In one embodiment, the invention provides a neutralising antibody havingspecificity for human IL-17A and human IL-17F, comprising a light chain,wherein the variable domain of the light chain comprises the sequencegiven in SEQ ID NO:4 or SEQ ID NO:7 for CDR-L1, the sequence given inSEQ ID NO:5 or SEQ ID NO:8 for CDR-L2 and the sequence given in SEQ IDNO:6 for CDR-L3.

It will be appreciated that one or more amino acid substitutions may bemade to the CDRs provided by the invention without significantlyaltering the ability of the antibody to bind to IL-17A and IL-17F and toneutralise IL-17A and IL-17F activity. The effect of any amino acidsubstitutions on binding and neutralisation can be readily tested by oneskilled in the art, for example by using the methods described herein.Accordingly, the invention provides an antibody comprising one or moreCDRs selected from CDR-H1 (SEQ ID NO:1), CDR-H2 (SEQ ID NO:2), CDR-H3(SEQ ID NO:3), CDR-L1 (SEQ ID NO:4 or SEQ ID NO:7), CDR-L2 (SEQ ID NO:5or SEQ ID NO:8) and CDR-L3 (SEQ ID NO:6) in which one or more aminoacids in one or more of the CDRs has been substituted with another aminoacid. It will also be appreciated that the length of one or more of theCDRs may be altered without significantly altering the ability of theantibody to bind to IL-17A and IL-17F and to neutralise IL-17A andIL-17F activity.

In another embodiment, the invention provides a neutralising antibodyhaving specificity for human IL-17A and human IL-17F, comprising a heavychain, wherein at least two of CDR-H1, CDR-H2 and CDR-H3 of the variabledomain of the heavy chain are selected from the following: the sequencegiven in SEQ ID NO:1 for CDR-H1, the sequence given in SEQ ID NO:2 forCDR-H2 and the sequence given in SEQ ID NO:3 for CDR-H3. For example,the antibody may comprise a heavy chain wherein CDR-H1 has the sequencegiven in SEQ ID NO:1 and CDR-H2 has the sequence given in SEQ ID NO:2.Alternatively, the antibody may comprise a heavy chain wherein CDR-H1has the sequence given in SEQ ID NO:1 and CDR-H3 has the sequence givenin SEQ ID NO:3, or the antibody may comprise a heavy chain whereinCDR-H2 has the sequence given in SEQ ID NO:2 and CDR-H3 has the sequencegiven in SEQ ID NO:3. For the avoidance of doubt, it is understood thatall permutations are included.

In another embodiment, the invention provides a neutralising antibodyhaving specificity for human IL-17A and human IL-17F, comprising a lightchain, wherein at least two of CDR-L1, CDR-L2 and CDR-L3 of the variabledomain of the light chain are selected from the following: the sequencegiven in SEQ ID NO:4 or SEQ ID NO:7 for CDR-L1, the sequence given inSEQ ID NO:5 or 8 for CDR-L2 and the sequence given in SEQ ID NO:6 forCDR-L3. For example, the antibody may comprise a light chain whereinCDR-L1 has the sequence given in SEQ ID NO:4 and CDR-L2 has the sequencegiven in SEQ ID NO:5. Alternatively, the antibody may comprise a lightchain wherein CDR-L1 has the sequence given in SEQ ID NO:4 and CDR-L3has the sequence given in SEQ ID NO:6, or the antibody may comprise alight chain wherein CDR-L2 has the sequence given in SEQ ID NO:5 andCDR-L3 has the sequence given in SEQ ID NO:6. For the avoidance ofdoubt, it is understood that all permutations are included.

In one embodiment, an antibody according to the invention comprises aheavy chain, wherein the variable domain of the heavy chain comprisesthe sequence given in SEQ ID NO:1 for CDR-H1, the sequence given in SEQID NO:2 for CDR-H2 and the sequence given in SEQ ID NO:3 for CDR-H3 anda light chain wherein the variable domain of the light chain comprisesthe sequence given in SEQ ID NO:4 for CDR-L1, the sequence given in SEQID NO:5 for CDR-L2 and the sequence given in SEQ ID NO:6 for CDR-L3.

In one embodiment, an antibody according to the invention comprises aheavy chain, wherein the variable domain of the heavy chain comprisesthe sequence given in SEQ ID NO:1 for CDR-H1, the sequence given in SEQID NO:2 for CDR-H2 and the sequence given in SEQ ID NO:3 for CDR-H3 anda light chain wherein the variable domain of the light chain comprisesthe sequence given in SEQ ID NO:7 for CDR-L1, the sequence given in SEQID NO:8 for CDR-L2 and the sequence given in SEQ ID NO:6 for CDR-L3.

In one embodiment, an antibody of the invention comprises a heavy chain,wherein the variable domain of the heavy chain comprises three CDRswherein the sequence of CDR-H1 has at least 60% identity or similarityto the sequence given in SEQ ID NO:1, CDR-H2 has at least 60% identityor similarity to the sequence given in SEQ ID NO:2 and/or CDR-H3 has atleast 60% identity or similarity to the sequence given in SEQ ID NO:3.In another embodiment, an antibody of the invention comprises a heavychain, wherein the variable domain of the heavy chain comprises threeCDRs wherein the sequence of CDR-H1 has at least 70%, 80%, 90%, 95% or98% identity or similarity to the sequence given in SEQ ID NO:1, CDR-H2has at least 70%, 80%, 90%, 95% or 98% identity or similarity to thesequence given in SEQ ID NO:2 and/or CDR-H3 has at least 70%, 80%, 90%,95% or 98% identity or similarity to the sequence given in SEQ ID NO:3.

In another embodiment, an antibody of the invention comprises a lightchain, wherein the variable domain of the light chain comprises threeCDRs wherein the sequence of CDR-L1 has at least 60% identity orsimilarity to the sequence given in SEQ ID NO:4, CDR-L2 has at least 60%identity or similarity to the sequence given in SEQ ID NO:5 and/orCDR-L3 has at least 60% identity or similarity to the sequence given inSEQ ID NO:6. In another embodiment, an antibody of the inventioncomprises a light chain, wherein the variable domain of the heavy chaincomprises three CDRs wherein the sequence of CDR-L1 has at least 70%,80%, 90%, 95% or 98% identity or similarity to the sequence given in SEQID NO:4, CDR-L2 has at least 70%, 80%, 90%, 95% or 98% identity orsimilarity to the sequence given in SEQ ID NO:5, and/or CDR-L3 has atleast 70%, 80%, 90%, 95% or 98% identity or similarity to the sequencegiven in SEQ ID NO:6.

In another embodiment, an antibody of the invention comprises a lightchain, wherein the variable domain of the light chain comprises threeCDRs wherein the sequence of CDR-L1 has at least 60% identity orsimilarity to the sequence given in SEQ ID NO:4, CDR-L2 has at least 60%identity or similarity to the sequence given in SEQ ID NO:5 and/orCDR-L3 has at least 60% identity or similarity to the sequence given inSEQ ID NO:6. In another embodiment, an antibody of the inventioncomprises a light chain, wherein the variable domain of the heavy chaincomprises three CDRs wherein the sequence of CDR-L1 has at least 70%,80%, 90%, 95% or 98% identity or similarity to the sequence given in SEQID NO:7, CDR-L2 has at least 70%, 80%, 90%, 95% or 98% identity orsimilarity to the sequence given in SEQ ID NO:8, and/or CDR-L3 has atleast 70%, 80%, 90%, 95% or 98% identity or similarity to the sequencegiven in SEQ ID NO:6.

In one embodiment, an antibody of the invention comprises a light chain,wherein the variable domain of the light chain comprises the sequencegiven in SEQ ID NO:9 (gL7).

In another embodiment, an antibody of the invention comprises a lightchain, wherein the variable domain of the light chain comprises asequence having at least 60% identity or similarity to the sequencegiven in SEQ ID NO:9. In one embodiment, the antibody of the inventioncomprises a light chain, wherein the variable domain of the light chaincomprises a sequence having at least 70%, 80%, 90%, 95% or 98% identityor similarity to the sequence given in SEQ ID NO:9.

In one embodiment, an antibody of the invention comprises a light chain,wherein the variable domain of the light chain comprises the sequencegiven in SEQ ID NO:10 (gL57).

In another embodiment, an antibody of the invention comprises a lightchain, wherein the variable domain of the light chain comprises asequence having at least 60% identity or similarity to the sequencegiven in SEQ ID NO:10. In one embodiment, the antibody of the inventioncomprises a light chain, wherein the variable domain of the light chaincomprises a sequence having at least 70%, 80%, 90%, 95% or 98% identityor similarity to the sequence given in SEQ ID NO:10.

In one embodiment, an antibody of the invention comprises a heavy chain,wherein the variable domain of the heavy chain comprises the sequencegiven in SEQ ID NO:11 (gH9).

In another embodiment, an antibody of the invention comprises a heavychain, wherein the variable domain of the heavy chain comprises asequence having at least 60% identity or similarity to the sequencegiven in SEQ ID NO:11. In one embodiment, an antibody of the inventioncomprises a heavy chain, wherein the variable domain of the heavy chaincomprises a sequence having at least 70%, 80%, 90%, 95%, 96, 97, 98 or99% identity or similarity to the sequence given in SEQ ID NO:11.

In one embodiment, an antibody of the invention comprises a heavy chain,wherein the variable domain of the heavy chain comprises the sequencegiven in SEQ ID NO:11 and a light chain, wherein the variable domain ofthe light chain comprises the sequence given in SEQ ID NO:9.

In another embodiment of the invention, the antibody comprises a heavychain and a light chain, wherein the variable domain of the heavy chaincomprises a sequence having at least 60% identity or similarity to thesequence given in SEQ ID NO:11 and the variable domain of the lightchain comprises a sequence having at least 60% identity or similarity tothe sequence given in SEQ ID NO:9. Preferably, the antibody comprises aheavy chain, wherein the variable domain of the heavy chain comprises asequence having at least 70%, 80%, 90%, 95%, 96%, 97%, 98 or 99%identity or similarity to the sequence given in SEQ ID NO:11 and a lightchain, wherein the variable domain of the light chain comprises asequence having at least 70%, 80%, 90%, 95% 96, 97, 98 or 99% identityor similarity to the sequence given in SEQ ID NO:9.

In one embodiment, an antibody of the invention comprises a heavy chain,wherein the variable domain of the heavy chain comprises the sequencegiven in SEQ ID NO:11 and a light chain, wherein the variable domain ofthe light chain comprises the sequence given in SEQ ID NO:10.

In another embodiment of the invention, the antibody comprises a heavychain and a light chain, wherein the variable domain of the heavy chaincomprises a sequence having at least 60% identity or similarity to thesequence given in SEQ ID NO:11 and the variable domain of the lightchain comprises a sequence having at least 60% identity or similarity tothe sequence given in SEQ ID NO:10. Preferably, the antibody comprises aheavy chain, wherein the variable domain of the heavy chain comprises asequence having at least 70%, 80%, 90%, 95%, 96%, 97%, 98 or 99%identity or similarity to the sequence given in SEQ ID NO:11 and a lightchain, wherein the variable domain of the light chain comprises asequence having at least 70%, 80%, 90%, 95% 96, 97, 98 or 99% identityor similarity to the sequence given in SEQ ID NO:10.

In a preferred embodiment the antibody provided by the invention is aneutralising antibody having specificity for human IL-17A and humanIL-17F in which the heavy chain constant region comprises the human IgG1constant region. Accordingly, the invention provides an antibody inwhich the heavy chain comprises or consists of the sequence given in SEQID NO:15.

In one embodiment, of the invention, the antibody comprises a heavychain, wherein the heavy chain comprises a sequence having at least 60%identity or similarity to the sequence given in SEQ ID NO:15.Preferably, the antibody comprises a heavy chain, wherein the heavychain comprises a sequence having at least 70%, 80%, 90%, 95%, 97%, 98%,or 99% identity or similarity to the sequence given in SEQ ID NO:15.

In one embodiment, an antibody molecule according to the inventioncomprises a light chain comprising the sequence given in SEQ ID NO:12.

In one embodiment, of the invention, the antibody comprises a lightchain, wherein the light chain comprises a sequence having at least 60%identity or similarity to the sequence given in SEQ ID NO:12.Preferably, the antibody comprises a light chain, wherein the lightchain comprises a sequence having at least 70%, 80%, 90%, 95% or 98%identity or similarity to the sequence given in SEQ ID NO:12.

In one embodiment, the invention provides an antibody in which the heavychain comprises or consists of the sequence given in SEQ ID NO:15, andthe light chain comprises or consists of the sequence given in SEQ IDNO:12.

In one embodiment, of the invention, the antibody comprises a heavychain and a light chain, wherein the heavy chain comprises a sequencehaving at least 60% identity or similarity to the sequence given in SEQID NO:15 and the light chain comprises a sequence having at least 60%identity or similarity to the sequence given in SEQ ID NO:12.Preferably, the antibody comprises a heavy chain, wherein the heavychain comprises a sequence having at least 70%, 80%, 90%, 95% or 98%identity or similarity to the sequence given in SEQ ID NO:15 and a lightchain, wherein the light chain comprises a sequence having at least 70%,80%, 90%, 95% or 98% identity or similarity to the sequence given in SEQID NO:12.

In a preferred embodiment the antibody provided by the invention is aneutralising antibody having specificity for human IL-17A and humanIL-17F in which the heavy chain constant region comprises the human IgG1constant region. Accordingly, the invention provides an antibody inwhich the heavy chain comprises or consists of the sequence given in SEQID NO:16.

In one embodiment, of the invention, the antibody comprises a heavychain, wherein the heavy chain comprises a sequence having at least 60%identity or similarity to the sequence given in SEQ ID NO:16.Preferably, the antibody comprises a heavy chain, wherein the heavychain comprises a sequence having at least 70%, 80%, 90%, 95%, 97%, 98%,or 99% identity or similarity to the sequence given in SEQ ID NO:16.

In one embodiment, an antibody molecule according to the inventioncomprises a light chain comprising the sequence given in SEQ ID NO:13.

In one embodiment, of the invention, the antibody comprises a lightchain, wherein the light chain comprises a sequence having at least 60%identity or similarity to the sequence given in SEQ ID NO:13.Preferably, the antibody comprises a light chain, wherein the lightchain comprises a sequence having at least 70%, 80%, 90%, 95% or 98%identity or similarity to the sequence given in SEQ ID NO:13.

In one embodiment, the invention provides an antibody in which the heavychain comprises or consists of the sequence given in SEQ ID NO:16 andthe light chain comprises or consists of the sequence given in SEQ IDNO:13.

In one embodiment, of the invention, the antibody comprises a heavychain and a light chain, wherein the heavy chain comprises a sequencehaving at least 60% identity or similarity to the sequence given in SEQID NO:16 and the light chain comprises a sequence having at least 60%identity or similarity to the sequence given in SEQ ID NO:13.Preferably, the antibody comprises a heavy chain, wherein the heavychain comprises a sequence having at least 70%, 80%, 90%, 95% or 98%identity or similarity to the sequence given in SEQ ID NO:16 and a lightchain, wherein the light chain comprises a sequence having at least 70%,80%, 90%, 95% or 98% identity or similarity to the sequence given in SEQID NO:13.

In one embodiment, the invention provides an antibody in which the heavychain comprises or consists of the sequence given in SEQ ID NO:15 andthe light chain comprises or consists of the sequence given in SEQ IDNO:13.

In one embodiment, of the invention, the antibody comprises a heavychain and a light chain, wherein the heavy chain comprises a sequencehaving at least 60% identity or similarity to the sequence given in SEQID NO:15 and the light chain comprises a sequence having at least 60%identity or similarity to the sequence given in SEQ ID NO:13.Preferably, the antibody comprises a heavy chain, wherein the heavychain comprises a sequence having at least 70%, 80%, 90%, 95% or 98%identity or similarity to the sequence given in SEQ ID NO:15 and a lightchain, wherein the light chain comprises a sequence having at least 70%,80%, 90%, 95% or 98% identity or similarity to the sequence given in SEQID NO:13.

In one embodiment, the invention provides an antibody in which the heavychain comprises or consists of the sequence given in SEQ ID NO:16 andthe light chain comprises or consists of the sequence given in SEQ IDNO:12.

In one embodiment, of the invention, the antibody comprises a heavychain and a light chain, wherein the heavy chain comprises a sequencehaving at least 60% identity or similarity to the sequence given in SEQID NO:16 and the light chain comprises a sequence having at least 60%identity or similarity to the sequence given in SEQ ID NO:12.Preferably, the antibody comprises a heavy chain, wherein the heavychain comprises a sequence having at least 70%, 80%, 90%, 95% or 98%identity or similarity to the sequence given in SEQ ID NO:16 and a lightchain, wherein the light chain comprises a sequence having at least 70%,80%, 90%, 95% or 98% identity or similarity to the sequence given in SEQID NO:12.

Binding Affinity

The neutralising antibody molecule of any aspect of the inventionpreferably has a high binding affinity, preferably nanomolar, even morepreferably picomolar. It will be appreciated that the binding affinityof an antibody according to the invention for human IL-17A may bedifferent from the binding affinity of the same antibody for humanIL-17F and/or the IL-17A/F heterodimer.

In one example, the antibody molecule of the invention has an affinityfor IL-17A that is greater than its affinity for IL-17F. In one example,the antibody molecule of the invention has an affinity for IL-17A whichis at least 10 fold greater than its binding affinity for IL-17F. In oneexample, the antibody molecule of the invention has an affinity forIL-17A which is at least 50 fold greater than its binding affinity forIL-17F. In one example, the antibody molecule of the invention has anaffinity for IL-17A which is at least 100 fold greater than its bindingaffinity for IL-17F. In one example, the antibody molecule of theinvention has a nanomolar affinity for IL-17F and a picomolar affinityfor IL-17A.

In one example, the antibody molecule of the invention has an affinityfor IL-17F that is greater than its affinity for IL-17A. In one example,the antibody molecule of the invention has an affinity for IL-17F whichis at least 10 fold greater than its binding affinity for IL-17A. In oneexample, the antibody molecule of the invention has an affinity forIL-17F which is at least 50 fold greater than its binding affinity forIL-17A. In one example, the antibody molecule of the invention has anaffinity for IL-17F which is at least 100 fold greater than its bindingaffinity for IL-17A. In one example, the antibody molecule of theinvention has a picomolar affinity for IL-17A and a nanomolar affinityfor IL-17F.

In one example, the antibody molecule of the invention has an affinityfor IL-17A that is the same as its affinity for IL-17F. In one example,the antibody molecule of the invention has a nanomolar affinity for bothIL-17A and IL-17F. In one example, the antibody molecule of theinvention has a picomolar affinity for both IL-17A and IL-17F.

Affinity may be measured using any suitable method known in the art,including BIAcore™ using isolated natural or recombinant IL-17A andIL-17F which both exist as homodimers.

Preferably the antibody molecule of the invention has a binding affinityfor IL-17A of less than 10 nM. In one embodiment, the antibody moleculeof the invention has a binding affinity for IL-17A of less than 500 pM.In one embodiment, the antibody molecule of the invention has a bindingaffinity for IL-17A of 100 pM or less. In one embodiment, the antibodymolecule of the invention has a binding affinity for IL-17A of 20 pM orless. In one embodiment, the antibody of the invention has an affinityfor IL-17A of 16 pM. In one embodiment, the antibody molecule of theinvention has a binding affinity for IL-17A of 10 pM or less. In oneembodiment, the antibody molecule of the invention has a bindingaffinity for IL-17A of 5 pM or less. In one embodiment, the antibody ofthe invention has an affinity for IL-17A of 3.2 pM.

Preferably the antibody molecule of the invention has a binding affinityfor IL-17F of less than 10 nM. In one embodiment, the antibody of theinvention has an affinity for IL-17F of less than 2 nM. In oneembodiment, the antibody of the invention has an affinity for IL-17F of1.75 nM. In one embodiment, the antibody of the invention has anaffinity for IL-17F of less than 500 pM. In one embodiment, the antibodymolecule of the invention has a binding affinity for IL-17F of 100 pM orless. In one embodiment, the antibody of the invention has an affinityfor IL-17F of 50 pM or less. In one embodiment, the antibody of theinvention has an affinity for IL-17F of 23 pM. In one embodiment, theantibody molecule of the invention has a binding affinity for IL-17F of10 pM or less. In one embodiment, the antibody molecule of the inventionhas a binding affinity for IL-17F of 5 pM or less.

Preferably the antibody molecule of the invention has a binding affinityfor IL-17A/F heterodimer of 10 nM or less. In one embodiment, theantibody molecule of the invention has a binding affinity for IL-17A/Fheterodimer of 500 pM or less. In one embodiment, the antibody moleculeof the invention has a binding affinity for IL-17A/F heterodimer of 150pM or less. In one embodiment, the antibody molecule of the inventionhas a binding affinity for IL-17A/F heterodimer of 116 pM. In oneembodiment, the antibody molecule of the invention has a bindingaffinity for IL-17A/F heterodimer of better than 100 pM. In oneembodiment, the antibody molecule of the invention has a bindingaffinity for IL-17A/F heterodimer of 10 pM or less. In one embodiment,the antibody molecule of the invention has a binding affinity forIL-17A/F heterodimer of 5 pM or less.

In one embodiment, the antibody molecule of the invention has a bindingaffinity for cynomolgus IL-17F of less than 2 nM. In one embodiment, theantibody molecule of the invention has a binding affinity for cynomolgusIL-17F of 1.03 nM.

Cross-Blocking Antibodies

Antibodies which cross-block the binding of an antibody according to theinvention, in particular, an antibody comprising the heavy chainsequence gH9 (SEQ ID NO:11) and the light chain sequence gL57 (SEQ IDNO:10) or the light chain sequence gL7 (SEQ ID NO:9), is useful inneutralising IL-17A and IL-17F activity. Accordingly, the invention alsoprovides a neutralising antibody which binds human IL-17A and humanIL-17F, which cross-blocks the binding of any one of the antibodiesdescribed above to human IL-17A and/or human IL-17F and/or humanIL-17A/F heterodimer and/or is cross-blocked from binding IL-17A and/orIL-17F and/or human IL-17A/F heterodimer by any one of those antibodies.In one embodiment, such an antibody binds to the same epitope as anantibody described herein above. In another embodiment thecross-blocking neutralising antibody binds to an epitope which bordersand/or overlaps with the epitope bound by an antibody described hereinabove. In another embodiment the cross-blocking neutralising antibody ofthis aspect of the invention does not bind to the same epitope as anantibody of the invention or an epitope that borders and/or overlapswith said epitope.

Cross-blocking antibodies can be identified using any suitable method inthe art, for example by using competition ELISA or BIAcore where bindingof the cross blocking antibody to human IL-17A and/or human IL-17Fprevents the binding of an antibody of the invention or vice versa. Forsurface plasmon resonance (BIAcore), target molecules are immobilized ona solid phase and exposed to ligands in a mobile phase running along aflow cell. If ligand binding to the immobilized target occurs, the localrefractive index changes, leading to a change in SPR angle, which can bemonitored in real time by detecting changes in the intensity of thereflected light. The rates of change of the SPR signal can be analyzedto yield apparent rate constants for the association and dissociationphases of the binding reaction. The ratio of these values gives theapparent equilibrium constant (affinity) (see, e.g., Wolff et al.,Cancer Res. 53:2560 65 (1993)). Conditions suitable for surface plasmonresonance (BIAcore) assays are known in the art and described elsewhereherein.

ELISA-based methods for determining cross-blocking also are well knownin the art. A non-limiting, exemplary assay format suitable for bothIL-17A and IL-17F is as follows, illustrated with IL-17A. Ananti-IL-17A/F antibody (Ab-1) is coated (e.g., 50 μL of 1 μg/ml) onto a96-well ELISA plate [e.g. Coming 96 Well EIA/RIA Flat Bottom Microplate(Product #3590), Corning Inc., Acton, Mass.] for at least one hour.After this coating step the antibody solution is removed, the plate iswashed once or twice with wash solution (e.g., PBS and 0.05% Tween 20)and is then blocked using an appropriate blocking solution (e.g., PBS,1% BSA, 1% goat serum and 0.5% Tween 20) and procedures known in theart. Blocking solution is then removed from the ELISA plate and a secondanti-IL17A/F antibody (Ab-2), which is being tested for its ability tocross-block the coated antibody, is added in excess (e.g., 50 μl of 10μg/ml) in blocking solution to the appropriate wells of the ELISA plate.Following this, a limited amount (e.g. 50 μl of 10 ng/ml) of IL-17A inblocking solution is then added to the appropriate wells and the plateis incubated for at least one hour at room temperature while shaking.The plate is then washed 2-4 times with wash solution. An appropriateamount of a IL-17A detection reagent [e.g., biotinylated anti-IL-17polyclonal antibody that has been pre-complexed with an appropriateamount of a streptavidin-horseradish peroxidase (HRP) conjugate] inblocking solution is added to the ELISA plate and incubated for at leastone hour at room temperature. The plate is then washed with washsolution and is developed with an appropriate reagent [e.g. HRPsubstrates such as TMB (colorimetric) or various HRP luminescentsubstrates]. The background signal for the assay is defined as thesignal obtained in wells with the coated antibody (in this case Ab-1),second solution phase antibody (in this case Ab-2), IL-17A buffer only(i.e., no IL-17A) and IL-17A detection reagents. The positive controlsignal for the assay is defined as the signal obtained in wells with thecoated antibody (in this case Ab-1), second solution phase antibodybuffer only (i.e. no second solution phase antibody), IL-17A and IL-17Adetection reagents. Preferably, the ELISA assay is run in such a mannerso as to have the positive control signal be at least six times thebackground signal.

In one embodiment, there is provided a neutralising antibody which bindsto human IL-17A and human IL-17F, which cross-blocks the binding of anantibody whose heavy chain comprises the sequence gH9 (SEQ ID NO:11) andwhose light chain comprises the sequence gL57 (SEQ ID NO:10) to humanIL-17A and to human IL-17F. In one embodiment, the cross-blockingantibodies provided by the invention inhibit the binding of an antibodycomprising the heavy chain sequence gH9 (SEQ ID NO:11) and the lightchain sequence gL57 (SEQ ID NO:10) to IL-17A by greater than 80%,preferably by greater than 85%, more preferably by greater than 90%,even more preferably by greater than 95% and to IL-17F by greater than80%, preferably by greater than 85%, more preferably by greater than90%, even more preferably by greater than 95%.

In one embodiment, there is provided a neutralising antibody which bindsto human IL-17A and human IL-17F, which cross-blocks the binding of anantibody whose heavy chain comprises the sequence gH9 (SEQ ID NO:11) andwhose light chain comprises the sequence gL7 (SEQ ID NO:9) to humanIL-17A and to human IL-17F. In one embodiment, the cross-blockingantibodies provided by the invention inhibit the binding of an antibodycomprising the heavy chain sequence gH9 (SEQ ID NO:11) and the lightchain sequence gL7 (SEQ ID NO:9) to IL-17A by greater than 80%,preferably by greater than 85%, more preferably by greater than 90%,even more preferably by greater than 95% and to IL-17F by greater than80%, preferably by greater than 85%, more preferably by greater than90%, even more preferably by greater than 95%.

In one embodiment, there is provided a neutralising antibody which bindsto human IL-17A and human IL-17F, which cross-blocks the binding of anantibody whose heavy chain comprises the sequence gH9 (SEQ ID NO:11) andwhose light chain comprises the gL57 (SEQ ID NO:10) to human IL-17A andto human IL-17F and to human IL-17A/F heterodimer. In one embodiment,the cross-blocking antibodies provided by the invention inhibit thebinding of an antibody comprising the heavy chain sequence gH9 (SEQ IDNO:11) and the light chain sequence gL57 (SEQ ID NO:10) to IL-17A bygreater than 80%, preferably by greater than 85%, more preferably bygreater than 90%, even more preferably by greater than 95% and to IL-17Fby greater than 80%, preferably by greater than 85%, more preferably bygreater than 90%, even more preferably by greater than 95% and toIL-17A/F heterodimer to IL-17F by greater than 80%, preferably bygreater than 85%, more preferably by greater than 90%, even morepreferably by greater than 95%.

In one embodiment, there is provided a neutralising antibody which bindsto human IL-17A and human IL-17F, which cross-blocks the binding of anantibody whose heavy chain comprises the sequence gH9 (SEQ ID NO:11) andwhose light chain comprises the gL7 (SEQ ID NO:9) to human IL-17A and tohuman IL-17F and to human IL-17A/F heterodimer. In one embodiment, thecross-blocking antibodies provided by the invention inhibit the bindingof an antibody comprising the heavy chain sequence gH9 (SEQ ID NO:11)and the light chain sequence gL7 (SEQ ID NO:9) to IL-17A by greater than80%, preferably by greater than 85%, more preferably by greater than90%, even more preferably by greater than 95% and to IL-17F by greaterthan 80%, preferably by greater than 85%, more preferably by greaterthan 90%, even more preferably by greater than 95% and to IL-17A/Fheterodimer to IL-17F by greater than 80%, preferably by greater than85%, more preferably by greater than 90%, even more preferably bygreater than 95%.

In one embodiment, there is provided a neutralising antibody which bindsto human IL-17A and human IL-17F, which cross-blocks the binding of anantibody whose heavy chain comprises the sequence gH9 (SEQ ID NO:11) andwhose light chain comprises the sequence gL57 (SEQ ID NO:10) to humanIL-17A or to human IL-17F or human IL-17A/F heterodimer. In oneembodiment, the cross-blocking antibodies provided by the inventioninhibit the binding of an antibody comprising the heavy chain sequencegH9 (SEQ ID NO:11) and the light chain sequence gL57 (SEQ ID NO:10) toIL-17A or IL-17F or IL-17A/F by greater than 80%, preferably by greaterthan 85%, more preferably by greater than 90%, even more preferably bygreater than 95%.

In one embodiment, there is provided a neutralising antibody which bindsto human IL-17A and human IL-17F, which cross-blocks the binding of anantibody whose heavy chain comprises the sequence gH9 (SEQ ID NO:11) andwhose light chain comprises the sequence gL7 (SEQ ID NO:9) to humanIL-17A or to human IL-17F or human IL-17A/F heterodimer. In oneembodiment, the cross-blocking antibodies provided by the inventioninhibit the binding of an antibody comprising the heavy chain sequencegH9 (SEQ ID NO:11) and the light chain sequence gL7 (SEQ ID NO:9) toIL-17A or IL-17F or IL-17A/F by greater than 80%, preferably by greaterthan 85%, more preferably by greater than 90%, even more preferably bygreater than 95%.

Alternatively or in addition, neutralising antibodies according to thisaspect of the invention may be cross-blocked from binding to humanIL-17A and human IL-17F by an antibody comprising the heavy chainsequence gH9 (SEQ ID NO:11) and the light chain sequence gL57 (SEQ IDNO:10). Also provided therefore is a neutralising antibody moleculewhich binds to human IL-17A and to human IL-17F which is cross-blockedfrom binding human IL-17A and human IL-17F by an antibody comprising theheavy chain sequence gH9 (SEQ ID NO:11) and the light chain sequencegL57 (SEQ ID NO:10). In one embodiment, the neutralising antibodiesprovided by this aspect of the invention are inhibited from binding tohuman IL-17A and human IL-17F by an antibody comprising the heavy chainsequence gH9 (SEQ ID NO:11) and the light chain sequence gL57 (SEQ IDNO:10) by greater than 80%, preferably by greater than 85%, morepreferably by greater than 90%, even more preferably by greater than95%.

Alternatively or in addition, neutralising antibodies according to thisaspect of the invention may be cross-blocked from binding to humanIL-17A and human IL-17F by an antibody comprising the heavy chainsequence gH9 (SEQ ID NO:11) and the light chain sequence gL7 (SEQ IDNO:9). Also provided therefore is a neutralising antibody molecule whichbinds to human IL-17A and to human IL-17F which is cross-blocked frombinding human IL-17A and human IL-17F by an antibody comprising theheavy chain sequence gH9 (SEQ ID NO:11) and the light chain sequence gL7(SEQ ID NO:9). In one embodiment, the neutralising antibodies providedby this aspect of the invention are inhibited from binding to humanIL-17A and human IL-17F by an antibody comprising the heavy chainsequence gH9 (SEQ ID NO:11) and the light chain sequence gL7 (SEQ IDNO:9) by greater than 80%, preferably by greater than 85%, morepreferably by greater than 90%, even more preferably by greater than95%.

In another embodiment there is provided a neutralising antibody moleculewhich binds to human IL-17A and to human IL-17F which is cross-blockedfrom binding human IL-17A and human IL-17F and IL-17A/F heterodimer byan antibody comprising the heavy chain sequence gH9 (SEQ ID NO:11) andthe light chain sequence gL57 (SEQ ID NO:10). In one embodiment, theneutralising antibodies provided by this aspect of the invention areinhibited from binding to human IL-17A and human IL-17F and humanIL-17A/F heterodimer by an antibody comprising the heavy chain sequencegH9 (SEQ ID NO:11) and the light chain sequence gL57 (SEQ ID NO:10) bygreater than 80%, preferably by greater than 85%, more preferably bygreater than 90%, even more preferably by greater than 95%.

In another embodiment there is provided a neutralising antibody moleculewhich binds to human IL-17A and to human IL-17F which is cross-blockedfrom binding human IL-17A and human IL-17F and IL-17A/F heterodimer byan antibody comprising the heavy chain sequence gH9 (SEQ ID NO:11) andthe light chain sequence gL7 (SEQ ID NO:9). In one embodiment, theneutralising antibodies provided by this aspect of the invention areinhibited from binding to human IL-17A and human IL-17F and humanIL-17A/F heterodimer by an antibody comprising the heavy chain sequencegH9 (SEQ ID NO:11) and the light chain sequence gL7 (SEQ ID NO:9) bygreater than 80%, preferably by greater than 85%, more preferably bygreater than 90%, even more preferably by greater than 95%.

Also provided therefore is a neutralising antibody molecule which bindsto human IL-17A and to human IL-17F which is cross-blocked from bindinghuman IL-17A or human IL-17F or human IL-17A/F by an antibody comprisingthe heavy chain sequence gH9 (SEQ ID NO:11) and the light chain sequencegL57 (SEQ ID NO:10). In one embodiment, the neutralising antibodiesprovided by this aspect of the invention are inhibited from binding tohuman IL-17A or human IL-17F or human IL-17A/F by an antibody comprisingthe heavy chain sequence gH9 (SEQ ID NO:11) and the light chain sequencegL57 (SEQ ID NO:10) by greater than 80%, preferably by greater than 85%,more preferably by greater than 90%, even more preferably by greaterthan 95%.

Also provided therefore is a neutralising antibody molecule which bindsto human IL-17A and to human IL-17F which is cross-blocked from bindinghuman IL-17A or human IL-17F or human IL-17A/F by an antibody comprisingthe heavy chain sequence gH9 (SEQ ID NO:11) and the light chain sequencegL7 (SEQ ID NO:9). In one embodiment, the neutralising antibodiesprovided by this aspect of the invention are inhibited from binding tohuman IL-17A or human IL-17F or human IL-17A/F by an antibody comprisingthe heavy chain sequence gH9 (SEQ ID NO:11) and the light chain sequencegL7 (SEQ ID NO:9) by greater than 80%, preferably by greater than 85%,more preferably by greater than 90%, even more preferably by greaterthan 95%.

Epitopes of IL-17A/17-F

Also provided by the invention is a specific region or epitope of humanIL-17A and/or a specific region or epitope of human IL-17F and/or aspecific region or epitope of human IL-17A/F heterodimer which is boundby an antibody provided by the invention, in particular an antibodycomprising the heavy chain sequence gH9 (SEQ ID NO:11) and/or the lightchain sequence gL7 (SEQ ID NO:9) and/or the light chain sequence gL57(SEQ ID NO:10). The sequences for human IL-17A and human IL-17F areprovided herein in Figure [1] (SEQ ID NOS: 27 and 28).

Examples of epitopes of the invention, and methods of determining thoseepitopes, are provided in Examples 5-7 of U.S. Pat. No. 8,679,494 (Apr.23, 2008 priority date).

Any suitable method known in the art may be used to determine theresidues bound by an antibody provided by the invention e.g.hydrogen-deuterium exchange, site-directed mutagenesis, massspectrometry, NMR and X-ray crystallography. See for example the methodsdescribed in WO2007/149032.

The specific region or epitope of the human IL-17A polypeptide and/orthe specific region or epitope of the human IL-17F polypeptide and/orthe specific region or epitope of the human IL-17A/F heterodimer can beidentified by any suitable epitope mapping method known in the art incombination with any one of the antibodies provided by the invention.Examples of such methods include screening peptides of varying lengthsderived from IL-17A and IL-17F for binding to the antibody of theinvention with the smallest fragment that can specifically bind to theantibody containing the sequence of the epitope recognised by theantibody. The IL-17 peptides may be produced synthetically or byproteolytic digestion of the appropriate IL-17 polypeptide. Peptidesthat bind the antibody can be identified by, for example, massspectrometric analysis. In another example, NMR spectroscopy can be usedto identify the epitope bound by an antibody of the invention. Inanother example, NMR spectroscopy can be used to identify residues whichinteract with an antibody of the invention. Once identified, theepitopic fragment which binds an antibody of the invention can be used,if required, as an immunogen to obtain additional neutralisingantibodies which bind the same epitope. In one embodiment, the inventionprovides a neutralising epitope of IL-17A which comprises or consists ofone or more of the residues selected from the group consisting of TYR44,ASN45, TRP51, ASN52 and ASP84 of human IL-17A (SEQ ID NO:27).

In one embodiment, the invention provides a neutralising epitope ofIL-17A which comprises or consists of one or more of the residuesselected from the group consisting of SER41, TYR44, ASN45, TRP51, ASN52,HIS54, ARG72, HIS73 and ASP84 of human IL-17A (SEQ ID NO:27).

In one embodiment, the invention provides a neutralising epitope ofIL-17A which comprises or consists of one or more of the residuesselected from the group consisting of SER41, TYR44, ASN45, ARG46, TRP51,ASN52, HIS54, ARG72, HIS73, ASP84, HIS86, VAL128, HIS129 and VAL131 ofhuman IL-17A (SEQ ID NO:27).

In one embodiment, the invention provides a neutralising epitope ofIL-17A which comprises one or more of the residues selected from thegroup consisting of TYR44, ASN45, TRP51, ASN52 and ASP84 of human IL-17A(SEQ ID NO:27) and optionally one or more of the residues selected fromthe group consisting of SER41, ARG46, HIS54, ARG72, HIS73, HIS86,VAL128, HIS129 and VAL131 of human IL-17A (SEQ ID NO:27).

In one embodiment, the invention provides a neutralising epitope ofIL-17A which comprises amino acid residues TYR44, ASN45, TRP51, ASN52and ASP84 of human IL-17A (SEQ ID NO:27) and optionally one or more ofthe residues selected from the group consisting of SER41, ARG46, HIS54,ARG72, HIS73, HIS86, VAL128, HIS129 and VAL131 of human IL-17A (SEQ IDNO:27).

IL-17A is a dimer, and in various embodiments, the epitope bound by theantibody comprises one or more residues selected from the groupconsisting of ARG72, HIS73, ASP80, GLY81, ASN82, ASP84, HIS86, VAL128,HIS129, and VAL131 (of SEQ ID NO: 27) from the first chain of the dimer,and one or more residues selected from the group consisting of SER41,TYR44, ASN45, ARG46, TRP51, ASN52, and HIS54 (e.g., selected from thegroup consisting of SER41, TYR44, ASN45, and ARG46) (of SEQ ID NO: 27)from the second chain of the dimer.

In various embodiments, the neutralizing antibody specifically binds anepitope of human IL-17A comprising or consisting of one or more of theresidues L74, Y85, H73, N82 and R72, preferably L74 and Y85 of SEQ IDNO:27.

In various embodiments, the neutralizing antibody specifically binds anepitope of human IL-17A (e.g., the sequence of which is set forth inGenBank Accession No. Q16552) comprising or consisting of one or more ofthe residues L74 and G75.

The invention also provides a novel neutralising epitope of human IL-17F(SEQ ID NO:28) which comprises or consists of one or more of thefollowing residues: SER39, MET40, SER41, ARG42, ARG47, ASN53, ARG73,ASN74, LEU75, LYS83, GLU84, ASP85, ILE86, SER87, MET88, ASN89, VAL91,PRO92, GLN94, THR126, PRO127, VAL128.

The invention also provides a novel neutralising epitope of human IL-17F(SEQ ID NO:28) which comprises or consists of one or more of thefollowing residues: SER39, MET40, SER41, ARG42, ARG47, ASN53, CYS72,ARG73, ASN74, LEU75, LYS83, GLU84, ASP85, ILE86, SER87, MET88, ASN89,SER90, VAL91, PRO92, GLN94, THR119, CYS122, VAL125, THR126, PRO127,VAL128.

In one embodiment, the neutralising epitope of human IL-17F (SEQ IDNO:28) comprises or consists of one or more of the following residues:SER39, MET40, SER41, ARG42, ARG47, ASN53, ARG73, ASN74, LEU75, LYS83,GLU84, ASP85, ILE86, SER87, MET88, ASN89, VAL91, PRO92, GLN94, THR126,PRO127, VAL128.

In one embodiment, the neutralising epitope of human IL-17F (SEQ IDNO:28) comprises or consists of (or further comprises or furtherconsists of) one or more of the following residues: GLN71, CYS72, ILE86,ASN89, SER90 and VAL128, for example, from a first chain in an IL17Fdimer.

In one embodiment, the neutralising epitope of human IL-17F (SEQ IDNO:28) comprises or consists of (or further comprises or furtherconsists of) one or more of the following residues: ARG47, for example,from a second chain in an IL17F dimer.

In one embodiment, the neutralising epitope of human IL-17F (SEQ IDNO:28) comprises or consists of one or more of the following residues:GLN71, CYS72, ASN74, LEU75, ILE86, ASN89, SER90, PRO92, VAL128, HIS131and GLN133, for example, from a first chain in an IL17F dimer.

In one embodiment, the neutralising epitope of human IL-17F (SEQ IDNO:28) comprises or consists of (or further comprises or furtherconsists of) one or more of the following residues: ARG37, SER39, SER41and ARG47, for example, from a second chain in an IL17F dimer.

In one embodiment, the neutralising epitope of human IL-17F (SEQ IDNO:28) comprises or consists of one or more of the following residues:GLN71, CYS72, ARG73, ASN74, LEU75, ILE86, SER87 ASN89, SER90, VAL91,PRO92, VAL128, HIS131 and GLN133, for example, from a first chain in anIL17F dimer.

In one embodiment, the neutralising epitope of human IL-17F (SEQ IDNO:28) comprises or consists of (or further comprises or furtherconsists of) one or more of the following residues: ASN33, GLN36, ARG37,SER39, SER41, ARG42, ILE44 and ARG47, for example, from a second chainin an IL17F dimer.

In one embodiment, the neutralising epitope of human IL-17F (SEQ IDNO:28) comprises or consists of one or more of the following residues:GLN12, LYS13, SER24, ISO32, ASN33 GLU34, ASN35, GLN36, VAL38, SER46,ASN53, TYR54, GLN69, ISO78, ASP85, SER87, MET88, ASM89, GLN94, LYS103and THR126.

In one embodiment, the neutralising epitope of human IL-17F (SEQ IDNO:28) comprises or consists of one or more of the following residues:GLN12, SER24, ASN33, GLU34, GLN36, VAL38, ASN53, TYR54, ASP85, MET88,ASM89, and THR126.

In one embodiment, the neutralising epitope of human IL-17F (SEQ IDNO:28) comprises or consists of one or more of the following residues:GLN12, SER24, ASN33, GLU34, ASP85 and MET88.

In one embodiment, the neutralising epitope of human IL-17F (SEQ IDNO:28) comprises or consists of amino acids V33 to V38 inclusive.

In one embodiment, the neutralising epitope of human IL-17F (SEQ IDNO:28) comprises or consists of amino acids V87 to Q94 inclusive.

In one embodiment, the neutralising epitope of IL-17F (SEQ ID NO:28)further comprises one or more of the following residues: ILE129, HIS130,H131, V132, Q133.

In one embodiment, there is provided one or more neutralising epitopesof human IL-17F (SEQ ID NO:28) that each independently comprise orconsist of amino acids V33 to V38 inclusive and/or V87 to Q94 inclusive.

In various embodiments, the antibody specifically binds an epitope ofhuman IL-17F comprising or consisting of R73, 186, N89, and R47 of SEQID NO: 28.

In various embodiments, the neutralizing antibody specifically binds anepitope of human IL-17F (e.g., the sequence of which is set forth inGenBank Accession No. Q96PD4) comprising or consisting of one or more ofthe residues L75 and G76.

In various embodiments, the antibody specifically binds an epitope ofhuman IL-17F comprising or consisting of S39, S41, N89, C72, N74, L75,S90, V91, P92, V198 of SEQ ID NO: 28.

In various embodiments, the epitope bound by the antibody comprises oneor more residues selected from the group consisting of GLN71, CYS72,ARG73, ASN74, LEU75, ILE86, SER87, ASN89, SER90, VAL91, PRO92, VAL128,HIS131, and GLN133 (of SEQ ID NO: 28) from the first chain of the dimer,and one or more residues selected from the group consisting of ASN33,GLN36, ARG37, SER39, SER41, ARG42, ILE44, ARG47 (of SEQ ID NO: 28) fromthe second chain of the dimer.

In one embodiment, the epitope is defined as amino acid residues locatedwithin 4 Angstroms, 3.5 Angstroms, or 3.0 Angstroms of a binding entity,such as an antibody or fragment.

The invention also provides epitopic fragments of IL-17A that can beused, if required, as an immunogen to obtain neutralising antibodieswhich bind to the neutralising epitope of IL-17A.

For example, epitopic fragments comprising one or more of the amino acidresidues of IL-17A provided herein above may be used as an immunogen.

The invention also provides epitopic fragments of IL-17F that can beused, if required, as an immunogen to obtain neutralising antibodieswhich bind to the neutralising epitope of IL-17F.

For example, epitopic fragments comprising one or more of the amino acidresidues of IL-17F provided herein above may be used as an immunogen.

The invention also provides antibodies which bind to, and/or interactwith, a neutralising epitope provided by the invention. It will beappreciated that an antibody can interact directly or indirectly with anepitope of the invention, e.g. by direct binding or by allostericinteraction.

In one embodiment, the invention provides antibodies which bind to,and/or interact with, a neutralising epitope of IL-17A provided by theinvention.

Accordingly, in one embodiment, the invention provides a neutralisingantibody which binds human IL-17A and human IL-17F that binds to, and/orinteracts with, an epitope of human IL-17A comprising or consisting ofone or more of the residues selected from the group consisting of TYR44,ASN45, TRP51, ASN52 and ASP84 of human IL-17A (SEQ ID NO:27).

In one embodiment, the invention provides a neutralising antibody whichbinds human IL-17A and human IL-17F that binds to an epitope of humanIL-17A comprising ASN52 of human IL-17A (SEQ ID NO:27).

In one embodiment, the invention provides a neutralising antibody whichbinds human IL-17A and human IL-17F that binds to an epitope of humanIL-17A comprising ASN52 and ASP84 of human IL-17A (SEQ ID NO:27).

In one embodiment, the invention provides a neutralising antibody whichbinds human IL-17A and human IL-17F that binds to an epitope of humanIL-17A comprising ARG46 and HIS54 of human IL-17A (SEQ ID NO:27).

In one embodiment, the invention provides a neutralising antibody whichbinds human IL-17A and human IL-17F that binds to an epitope of humanIL-17A which comprises or consists of one or more of the residuesselected from the group consisting of SER41, ASN52, ARG72, HIS73 andASP84 of human IL-17A (SEQ ID NO:27).

In one embodiment, the invention provides a neutralising antibody whichbinds human IL-17A and human IL-17F that binds to an epitope of humanIL-17A which comprises or consists of one or more of the residuesselected from the group consisting of SER41, TYR44, ASN45, ARG46, TRP51,ASN52, HIS54, ARG72, HIS73, ASP84, HIS86, VAL128, HIS129 and VAL131 ofhuman IL-17A (SEQ ID NO:27).

In one embodiment, the invention provides antibodies which bind to,and/or interact with, a neutralising epitope of IL-17F provided by theinvention.

Accordingly, in one embodiment, the invention provides a neutralisingantibody which binds human IL-17F that binds to an epitope of humanIL-17F comprising one or more of the following residues: SER39, MET40,SER41, ARG42, ARG47, ASN53, ARG73, ASN74, LEU75, LYS83, GLU84, ASP85,ILE86, SER87, MET88, ASN89, SER90, VAL91, PRO92, GLN94, THR126, PRO127,VAL128 of IL-17F (SEQ ID NO:28).

In one embodiment, the invention provides a neutralising antibody whichbinds human IL-17F that binds to an epitope of human IL-17F within oneor more of the following regions: (i) 39-42 (SER39, MET40, SER41, ARG42)(ii) 47 (ARG47) (iii) 53 (ASN53) (iv) 72-75 (CYS72, ARG73, ASN74, LEU75)(v) 83-92 (LYS83, GLU84, ASP85, ILE86, SER87, MET88, ASN89, SER90,VAL91, PRO92) (vi) 94 (GLN94) (vii) 119 (THR119) (viii) 122 (CYS122)(ix) 125-128 (VAL125, THR126, PRO127, VAL128).

In one embodiment, an antibody of the invention binds human IL-17A andhuman IL-17F. In one embodiment, an antibody of the invention bindshuman IL-17A/F heterodimer. In one embodiment, an antibody of theinvention binds human IL-17A and human IL-17A/F heterodimer. In oneembodiment, an antibody of the invention binds human IL-17F and humanIL-17A/F heterodimer. In a preferred embodiment, an antibody of theinvention binds human IL-17A, human IL-17F and human IL-17A/Fheterodimer.

In one embodiment, the invention provides a neutralising antibody whichbinds human IL-17A and IL-17F that binds to an epitope of human IL-17Fwithin one or more of the following regions: (i) 39-42 (SER39, MET40,SER41, ARG42) (ii) 47 (ARG47) (iii) 53 (ASN53) (iv) 72-75 (CYS72, ARG73,ASN74, LEU75) (v) 83-92 (LYS83, GLU84, ASP85, ILE86, SER87, MET88,ASN89, SER90, VAL91, PRO92) (vi) 94 (GLN94) (vii) 119 (THR119) (viii)122 (CYS 122) (ix) 125-128 (VAL125, THR126, PRO127, VAL128).

Accordingly, in one embodiment, the invention provides a neutralisingantibody which binds human IL-17A and human IL-17F that binds to, and/orinteracts with, an epitope of human IL-17F comprising or consisting ofone or more of the residues selected from the group consisting of SER39,MET40, SER41, ARG42, ARG47, ASN53, ARG73, ASN74, LEU75, LYS83, GLU84,ASP85, ILE86, SER87, MET88, ASN89, SER90, VAL91, PRO92, GLN94, THR126,PRO127, VAL128 of SEQ ID NO:28 (IL-17F).

In one embodiment, the invention provides a neutralising antibody whichbinds human IL-17A and human IL-17F that binds, and/or interacts with,an epitope of human IL-17A which comprises or consists of one or more ofthe residues selected from the group consisting of SER41, TYR44, ASN45,ARG46, TRP51, ASN52, HIS54, ARG72, HIS73, ASP84, HIS86, VAL128, HIS129and VAL131 of human IL-17A (SEQ ID NO:27) and binds to, and/or interactswith, an epitope of human IL-17F comprising or consisting of one or moreof the residues selected from the group consisting of SER39, MET40,SER41, ARG42, ARG47, ASN53, ARG73, ASN74, LEU75, LYS83, GLU84, ASP85,ILE86, SER87, MET88, ASN89, SER90, VAL91, PRO92, GLN94, THR126, PRO127,VAL128 of SEQ ID NO:28 (IL-17F).

In one embodiment, the invention provides a neutralising antibody whichbinds human IL-17A and human IL-17F that binds to, and/or interactswith, an epitope of human IL-17F comprising or consisting of one or moreof the residues selected from the group consisting of SER39, SER41,ASN74, LEU75, ASN89, SER90, VAL91, PRO92 and VAL128 of SEQ ID NO:28(IL-17F).

Accordingly, in one embodiment, the invention provides a neutralisingantibody which binds human IL-17A and human IL-17F that binds to, and/orinteracts with, an epitope of human IL-17F comprising or consisting ofone or more of the residues selected from the group consisting of ARG47,ARG73, LEU75 and ILE86 of SEQ ID NO:28 (IL-17F).

Accordingly, in one embodiment, the invention provides a neutralisingantibody which binds human IL-17A and human IL-17F that binds to, and/orinteracts with, an epitope of human IL-17F comprising LEU75 of SEQ IDNO:28 (IL-17F).

Isolated DNA Sequences of Antibodies

The invention also provides an isolated DNA comprising a nucleic acidsequence encoding the heavy and/or light chain(s) of an antibodymolecule of the invention. Preferably, the DNA sequence encodes theheavy or the light chain of an antibody molecule of the invention. TheDNA of the invention may comprise synthetic DNA, for instance producedby chemical processing, cDNA, genomic DNA or any combination thereof.

DNA comprising nucleic acid sequences which encode an antibody moleculeof the invention can be obtained by methods well known to those skilledin the art. For example, DNA comprising nucleic acid sequences codingfor part or all of the antibody heavy and light chains may besynthesised as desired from the determined DNA sequences or on the basisof the corresponding amino acid sequences.

DNA coding for acceptor framework sequences is widely available to thoseskilled in the art and can be readily synthesised on the basis of theirknown amino acid sequences.

Standard techniques of molecular biology may be used to prepare DNAsequences coding for the antibody molecule of the invention. Desired DNAsequences may be synthesised completely or in part using oligonucleotidesynthesis techniques. Site-directed mutagenesis and polymerase chainreaction (PCR) techniques may be used as appropriate.

Examples of suitable sequences are provided in SEQ ID NO:18; SEQ IDNO:19; SEQ ID NO:20; SEQ ID NO:21; SEQ ID NO:22; SEQ ID NO:23; SEQ IDNO:24; SEQ ID NO:25; and SEQ ID NO:26. The invention also relates to acloning or expression vector comprising one or more DNA sequences of theinvention. Accordingly, the invention provides a cloning or expressionvector comprising one or more DNA sequences encoding an antibody of theinvention. Preferably, the cloning or expression vector comprises twoDNA sequences, encoding the light chain and the heavy chain of theantibody molecule of the invention, respectively, along with suitablesignal sequences. Preferably, a vector according to the inventioncomprises the sequences given in SEQ ID NO:21 and SEQ ID NO:24. In oneembodiment, a vector according to the invention comprises the sequencesgiven in SEQ ID NO:21 and SEQ ID NO:24.

General methods by which the vectors may be constructed, transfectionmethods and culture methods are well known to those skilled in the art.In this respect, reference is made to “Current Protocols in MolecularBiology”, 1999, F. M. Ausubel (ed), Wiley Interscience, New York and theManiatis Manual produced by Cold Spring Harbor Publishing.

Also the invention provides a host cell comprising one or more cloningor expression vectors comprising one or more DNA sequences encoding anantibody of the invention. Any suitable host cell/vector system may beused for expression of the DNA sequences encoding the antibody moleculeof the invention. Bacterial, for example E. coli, and other microbialsystems may be used or eukaryotic, for example mammalian, host cellexpression systems may also be used. Suitable mammalian host cellsinclude CHO, myeloma or hybridoma cells.

The invention also provides a process for the production of an antibodymolecule according to the invention comprising culturing a host cellcontaining a vector of the invention under conditions suitable forleading to expression of protein from DNA encoding the antibody moleculeof the invention, and isolating the antibody molecule.

The antibody molecule may comprise only a heavy or light chainpolypeptide, in which case only a heavy chain or light chain polypeptidecoding sequence needs to be used to transfect the host cells. Forproduction of products comprising both heavy and light chains, the cellline may be transfected with two vectors, a first vector encoding alight chain polypeptide and a second vector encoding a heavy chainpolypeptide. Alternatively, a single vector may be used, the vectorincluding sequences encoding light chain and heavy chain polypeptides.

Conjugation with Effector Molecules

If desired, an antibody for use in the invention may be conjugated toone or more effector molecule(s). It will be appreciated that theeffector molecule may comprise a single effector molecule or two or moresuch molecules so linked as to form a single moiety that can be attachedto the antibodies of the invention. Where it is desired to obtain anantibody fragment linked to an effector molecule, this may be preparedby standard chemical or recombinant DNA procedures in which the antibodyfragment is linked either directly or via a coupling agent to theeffector molecule. Techniques for conjugating such effector molecules toantibodies are well known in the art (see, Hellstrom et al., ControlledDrug Delivery, 2nd Ed., Robinson et al., eds., 1987, pp. 623-53; Thorpeet al., 1982, Immunol. Rev., 62:119-58 and Dubowchik et al., 1999,Pharmacology and Therapeutics, 83, 67-123). Particular chemicalprocedures include, for example, those described in WO 93/06231, WO92/22583, WO 89/00195, WO 89/01476 and WO03031581. Alternatively, wherethe effector molecule is a protein or polypeptide the linkage may beachieved using recombinant DNA procedures, for example as described inWO 86/01533 and EP0392745.

The term effector molecule as used herein includes, for example,antineoplastic agents, drugs, toxins, biologically active proteins, forexample enzymes, other antibody or antibody fragments, synthetic ornaturally occurring polymers, nucleic acids and fragments thereof, e.g.,DNA, RNA and fragments thereof, radionuclides, particularly radioiodide,radioisotopes, chelated metals, nanoparticles and reporter groups suchas fluorescent compounds or compounds which may be detected by NMR orESR spectroscopy.

Examples of effector molecules may include cytotoxins or cytotoxicagents including any agent that is detrimental to (e.g. kills) cells.Examples include combrestatins, dolastatins, epothilones, staurosporin,maytansinoids, spongistatins, rhizoxin, halichondrins, roridins,hemiasterlins, taxol, cytochalasin B, gramicidin D, ethidium bromide,emetine, mitomycin, etoposide, tenoposide, vincristine, vinblastine,colchicin, doxorubicin, daunorubicin, dihydroxy anthracin dione,mitoxantrone, mithramycin, actinomycin D, 1-dehydrotestosterone,glucocorticoids, procaine, tetracaine, lidocaine, propranolol, andpuromycin and analogs or homologs thereof.

Effector molecules also include, but are not limited to, antimetabolites(e.g. methotrexate, 6-mercaptopurine, 6-thioguanine, cytarabine,5-fluorouracil decarbazine), alkylating agents (e.g. mechlorethamine,thioepa chlorambucil, melphalan, carmustine (BSNU) and lomustine (CCNU),cyclothosphamide, busulfan, dibromomannitol, streptozotocin, mitomycinC, and cis-dichlorodiamine platinum (II) (DDP) cisplatin),anthracyclines (e.g. daunorubicin (formerly daunomycin) anddoxorubicin), antibiotics (e.g. dactinomycin (formerly actinomycin),bleomycin, mithramycin, anthramycin (AMC), calicheamicins orduocarmycins), and anti-mitotic agents (e.g. vincristine andvinblastine).

Other effector molecules may include chelated radionuclides such as¹¹¹In and ⁹⁰Y, Lu¹⁷⁷, Bismuth²¹³, Californium²⁵², Iridium¹⁹² andTungsten¹⁸⁸/Rhenium¹⁸⁸; or drugs such as but not limited to,alkylphosphocholines, topoisomerase I inhibitors, taxoids and suramin.

Other effector molecules include proteins, peptides and enzymes. Enzymesof interest include, but are not limited to, proteolytic enzymes,hydrolases, lyases, isomerases, transferases. Proteins, polypeptides andpeptides of interest include, but are not limited to, immunoglobulins,toxins such as abrin, ricin A, pseudomonas exotoxin, or diphtheriatoxin, a protein such as insulin, tumour necrosis factor, α-interferon,β-interferon, nerve growth factor, platelet derived growth factor ortissue plasminogen activator, a thrombotic agent or an anti-angiogenicagent, e.g., angiostatin or endostatin, or, a biological responsemodifier such as a lymphokine, interleukin-1 (IL-1), interleukin-2(IL-2), interleukin-6 (IL-6), granulocyte macrophage colony stimulatingfactor (GM-CSF), granulocyte colony stimulating factor (G-CSF), nervegrowth factor (NGF) or other growth factor and immunoglobulins.

Other effector molecules may include detectable substances useful forexample in diagnosis. Examples of detectable substances include variousenzymes, prosthetic groups, fluorescent materials, luminescentmaterials, bioluminescent materials, radioactive nuclides, positronemitting metals (for use in positron emission tomography), andnonradioactive paramagnetic metal ions. See generally U.S. Pat. No.4,741,900 for metal ions which can be conjugated to antibodies for useas diagnostics. Suitable enzymes include horseradish peroxidase,alkaline phosphatase, beta-galactosidase, or acetylcholinesterase;suitable prosthetic groups include streptavidin, avidin and biotin;suitable fluorescent materials include umbelliferone, fluorescein,fluorescein isothiocyanate, rhodamine, dichlorotriazinylaminefluorescein, dansyl chloride and phycoerythrin; suitable luminescentmaterials include luminol; suitable bioluminescent materials includeluciferase, luciferin, and aequorin; and suitable radioactive nuclidesinclude ¹²⁵I, ¹³¹I, ¹¹¹In and ⁹⁹Tc.

In another example the effector molecule may increase the half-life ofthe antibody in vivo, and/or reduce immunogenicity of the antibodyand/or enhance the delivery of an antibody across an epithelial barrierto the immune system. Examples of suitable effector molecules of thistype include polymers, albumin, albumin binding proteins, or albuminbinding compounds, such as those described in WO05/117984.

Where the effector molecule is a polymer it may, in general, be asynthetic or a naturally occurring polymer, for example an optionallysubstituted straight or branched chain polyalkylene, polyalkenylene orpolyoxyalkylene polymer or a branched or unbranched polysaccharide,e.g., a homo- or hetero-polysaccharide.

Particular optional substituents which may be present on theabove-mentioned synthetic polymers include one or more hydroxy, methylor methoxy groups.

Particular examples of synthetic polymers include optionally substitutedstraight or branched chain poly(ethyleneglycol), poly(propyleneglycol)poly(vinylalcohol) or derivatives thereof, especially optionallysubstituted poly(ethyleneglycol) such as methoxypoly(ethyleneglycol) orderivatives thereof.

Particular naturally occurring polymers include lactose, amylose,dextran, glycogen or derivatives thereof.

“Derivatives” as used herein is intended to include reactivederivatives, for example thiol-selective reactive groups such asmaleimides and the like. The reactive group may be linked directly orthrough a linker segment to the polymer. It will be appreciated that theresidue of such a group will in some instances form part of the productas the linking group between the antibody fragment and the polymer.

The size of the polymer may be varied as desired, but will generally bein an average molecular weight range from 500 Da to 50000 Da, preferablyfrom 5000 to 40000 Da and more preferably from 20000 to 40000 Da. Thepolymer size may in particular be selected on the basis of the intendeduse of the product for example ability to localize to certain tissuessuch as tumors or extend circulating half-life (for review see Chapman,2002, Advanced Drug Delivery Reviews, 54, 531-545). Thus, for example,where the product is intended to leave the circulation and penetratetissue, for example for use in the treatment of a tumour, it may beadvantageous to use a small molecular weight polymer, for example with amolecular weight of around 5000 Da. For applications where the productremains in the circulation, it may be advantageous to use a highermolecular weight polymer, for example having a molecular weight in therange from 20000 Da to 40000 Da.

Particularly preferred polymers include a polyalkylene polymer, such asa poly(ethyleneglycol) or, especially, a methoxypoly(ethyleneglycol) ora derivative thereof, and especially with a molecular weight in therange from about 15000 Da to about 40000 Da.

In one example, antibodies for use in the invention are attached topoly(ethyleneglycol) (PEG) moieties. In one particular example theantibody is an antibody fragment and the PEG molecules may be attachedthrough any available amino acid side-chain or terminal amino acidfunctional group located in the antibody fragment, for example any freeamino, imino, thiol, hydroxyl or carboxyl group. Such amino acids mayoccur naturally in the antibody fragment or may be engineered into thefragment using recombinant DNA methods (see for example U.S. Pat. Nos.5,219,996; 5,667,425; WO98/25971). In one example, the antibody moleculeof the invention is a modified Fab fragment wherein the modification isthe addition to the C-terminal end of its heavy chain one or more aminoacids to allow the attachment of an effector molecule. Preferably, theadditional amino acids form a modified hinge region containing one ormore cysteine residues to which the effector molecule may be attached.Multiple sites can be used to attach two or more PEG molecules.

Preferably PEG molecules are covalently linked through a thiol group ofat least one cysteine residue located in the antibody fragment. Eachpolymer molecule attached to the modified antibody fragment may becovalently linked to the sulphur atom of a cysteine residue located inthe fragment. The covalent linkage will generally be a disulphide bondor, in particular, a sulphur-carbon bond. Where a thiol group is used asthe point of attachment appropriately activated effector molecules, forexample thiol selective derivatives such as maleimides and cysteinederivatives may be used. An activated polymer may be used as thestarting material in the preparation of polymer-modified antibodyfragments as described above. The activated polymer may be any polymercontaining a thiol reactive group such as an α-halocarboxylic acid orester, e.g. iodoacetamide, an imide, e.g., maleimide, a vinyl sulphoneor a disulphide. Such starting materials may be obtained commercially(for example from Nektar, formerly Shearwater Polymers Inc., Huntsville,Ala., USA) or may be prepared from commercially available startingmaterials using conventional chemical procedures. Particular PEGmolecules include 20K methoxy-PEG-amine (obtainable from Nektar,formerly Shearwater; Rapp Polymere; and SunBio) and M-PEG-SPA(obtainable from Nektar, formerly Shearwater).

In one embodiment, the antibody is a modified Fab fragment which isPEGylated, i.e., has PEG (poly(ethyleneglycol)) covalently attachedthereto, e.g. according to the method disclosed in EP 0948544 [see also“Poly(ethyleneglycol) Chemistry, Biotechnical and BiomedicalApplications”, 1992, J. Milton Harris (ed), Plenum Press, New York,“Poly(ethyleneglycol) Chemistry and Biological Applications”, 1997, J.Milton Harris and S. Zalipsky (eds), American Chemical Society,Washington D.C. and “Bioconjugation Protein Coupling Techniques for theBiomedical Sciences”, 1998, M. Aslam and A. Dent, Grove Publishers, NewYork; Chapman, A. 2002, Advanced Drug Delivery Reviews 2002,54:531-545]. In one example, PEG is attached to a cysteine in the hingeregion. In one example, a PEG modified Fab fragment has a maleimidegroup covalently linked to a single thiol group in a modified hingeregion. A lysine residue may be covalently linked to the maleimide groupand to each of the amine groups on the lysine residue may be attached amethoxypoly (ethyleneglycol) polymer having a molecular weight ofapproximately 20,000 Da. The total molecular weight of the PEG attachedto the Fab fragment may therefore be approximately 40,000 Da.

In one embodiment, a neutralising antibody molecule of the invention isa modified Fab fragment having at the C-terminal end of its heavy chaina modified hinge region containing at least one cysteine residue towhich an effector molecule is attached. In one embodiment, the inventionprovides a neutralising antibody molecule having specificity for humanIL-17A and human IL-17F, which is a modified Fab fragment having a heavychain comprising the sequence given in SEQ ID NO:11 and a light chaincomprising the sequence given in SEQ ID NO:9 or the sequence given inSEQ ID NO:10 and having at the C-terminal end of its heavy chain amodified hinge region containing at least one cysteine residue to whichan effector molecule is attached. Preferably the effector molecule isPEG and is attached using the methods described in (WO98/25971 andWO2004072116) whereby a lysyl-maleimide group is attached to thecysteine residue at the C-terminal end of the heavy chain, and eachamino group of the lysyl residue has covalently linked to it amethoxypoly(ethyleneglycol) residue having a molecular weight of about20,000 Da. The total molecular weight of the PEG attached to theantibody is therefore approximately 40,000 Da.

In another example effector molecules may be attached to antibodyfragments using the methods described in International patentapplications WO2005/003169, WO2005/003170 and WO2005/003171.

Pharmaceutical Compositions, Administration Regimens

As the antibodies of the invention are useful in the treatment and/orprophylaxis of a pathological condition, the invention also provides apharmaceutical or diagnostic composition comprising an antibody moleculeof the invention in combination with one or more of a pharmaceuticallyacceptable excipient, diluent or carrier. Accordingly, provided is theuse of an antibody according to the invention for the manufacture of amedicament. The composition will usually be supplied as part of asterile, pharmaceutical composition that will normally include apharmaceutically acceptable carrier. A pharmaceutical composition of theinvention may additionally comprise a pharmaceutically-acceptableadjuvant.

The invention also provides a process for preparation of apharmaceutical or diagnostic composition comprising adding and mixingthe antibody molecule of the invention together with one or more of apharmaceutically acceptable excipient, diluent or carrier.

The antibody molecule may be the sole active ingredient in thepharmaceutical or diagnostic composition or may be accompanied by otheractive ingredients including other antibody ingredients, for example,anti-TNF, anti-IL-1α, anti-T cell, anti-IFNγ or anti-LPS antibodies, ornon-antibody ingredients such as xanthines or a small moleculeinhibitor.

The pharmaceutical compositions preferably comprise a therapeuticallyeffective amount of the antibody of the invention. The term“therapeutically effective amount” as used herein refers to an amount ofa therapeutic agent needed to treat, ameliorate or prevent a targeteddisease or condition, or to exhibit a detectable therapeutic orpreventative effect.

The precise therapeutically effective amount for a human subject willdepend upon the severity of the disease state, the general health of thesubject, the age, weight and gender of the subject, diet, time andfrequency of administration, drug combination(s), reaction sensitivitiesand tolerance/response to therapy. This amount can be determined byroutine experimentation and is within the judgment of the clinician.Generally, a therapeutically effective amount will be from 0.01 mg/kg to50 mg/kg, preferably 0.1 mg/kg to 20 mg/kg (e.g., 5 mg/kg to 10 mg/kg,such as about 8 mg/kg). Pharmaceutical compositions may be convenientlypresented in unit dose forms containing a predetermined amount of anactive agent of the invention per dose. Unit doses may range from 10 mgto 1,000 mg (e.g., between 80 mg and 720 mg, between 100 mg and 680 mgor between 160 mg and 640 mg), preferably 8 mg, 16 mg, 32 mg, 40 mg, 80mg, 160 mg, 240 mg, 320 mg, 480 mg, 560 mg, and 640 mg.

In various embodiments of methods of treating psoriasis, such as plaquepsoriasis, the amount of neutralizing antibody administered to thesubject is an amount that achieves at least a 50% change, at least a 60%change, at least a 75% change (e.g., at least an 80% change, at least an85% change, at least a 90% change, or at least a 95% change) in lesionseverity score (LSS) compared to pre-treatment (i.e., LSS prior toadministration of the neutralizing antibody) at two, four, six, or eightweeks following administration of the antibody. Alternatively or inaddition, the amount of neutralizing antibody administered is an amountthat achieves at least a 50% change, at least a 60% change, at least a75% change (e.g., at least an 80% change, at least an 85% change, atleast a 90% change, or at least a 95% change) in Psoriasis Area andSeverity Index (PASI) compared to pre-treatment at two, four, six, oreight weeks following administration of the antibody. Alternatively orin addition the amount of neutralising antibody is an amount thatachieves at least a 50% change, a 60% change, a 75% change (e.g., an 80%change, an 85% change, a 90% change, or a 95% change) in PASI comparedto pre-treatment at two, four, six or eight weeks followingadministration of the antibody and which maintains or increases thechange in PASI response for an additional two, four, six, eight, ten,twelve, fourteen, sixteen, eighteen, twenty or more weeks followingadministration of the antibody.

Optionally, the amount of neutralizing antibody is an amount thatachieves at least a 50% change, a 60% change, a 75% change (e.g., an 80%change, an 85% change, a 90% change, or a 95% change) in PASI comparedto pre-treatment at two, four, six or eight weeks followingadministration of the antibody, and the PASI score does not change morethan 5%, more than 10%, more than 20%, more than 25%, more than 30%,more than 35%, or more than 40% toward baseline (pre-treatment level)for an additional two, four, six, eight, ten, twelve, fourteen, sixteen,eighteen, twenty or more weeks following administration of the antibody.

An alternative means of evaluating treatment of psoriasis is thePhysician's Global Assessment score. The PGA scoring system is based onlesion erythema, induration, and scale, with score assignments thatrange from clear to severe, typically using a 5 or 6-level scale See,e.g., Langley et al., J Am Acad Dermatol. 2004; 51(4):563-569. Invarious aspects, the method of treating psoriasis described hereinresults in a reduction of PGA score of at least 20%, at least 50%, or atleast 70% from baseline at week 2, week 6, week 8, and/or week 12following administration.

In various embodiments concerning treatment of psoriatic arthritis, theamount of neutralizing antibody administered to the subject is an amountthat achieves (i) at least a 50% change, at least a 60% change, at leasta 75% change (e.g., at least an 80% change, at least an 85% change, atleast a 90% change, or at least a 95% change) in lesion severity score(LSS) compared to pre-treatment (i.e., LSS prior to administration ofthe neutralizing antibody) at two, four, six, or eight weeks followingadministration of the antibody and/or (ii) at least a 50% change, atleast a 60% change, at least a 75% change (e.g., at least an 80% change,at least an 85% change, at least a 90% change, or at least a 95% change)in Psoriasis Area and Severity Index (PASI) compared to pre-treatment attwo, four, six, or eight weeks following administration of the antibodyand/or (iii) at least a 20% change, at least a 30%, at least a 50%, atleast 60% or at least a 70% change in American College of Rheumatology(“ACR”) response compared to pre-treatment at two, four, six, or eightweeks following administration of the antibody. Alternatively or inaddition, the amount of neutralising antibody is an amount that achievesthe aforementioned changes in LSS, PASI, and/or ACR scores at two, four,six or eight weeks following administration of the antibody andmaintains or increases the change in LSS, PASI, and/or ACR response foran additional two, four, six, eight, ten, twelve, fourteen, sixteen,eighteen, twenty or more weeks following administration of the antibody.Optionally, the amount of neutralizing antibody is an amount thatachieves the aforementioned change in LSS, PASI, and/or ACR score attwo, four, six or eight weeks following administration of the antibody,and the LSS, PASI, and/or ACR score does not change more than 5%, morethan 10%, more than 20%, more than 25%%, more than 30%, more than 35%,or more than 40% toward baseline (pre-treatment level) for an additionaltwo, four, six, eight, ten, twelve, fourteen, sixteen, eighteen, twentyor more weeks following administration of the antibody.

CA028_0496.g3 has been tested in patients following single intravenousdose administration over the dose range of 8 mg to 640 mg. CA028_0496.g3has also been tested as a repeat dose administration with differentdosing regimens involving a loading dose followed by maintenance dosesat weeks 3 and 6. A multiple dose regimen without a loading dose also iscontemplated as part of the invention.

It will be appreciated that a suitable dosage regimen for any givenanti-IL-17A/F antibody may be designed using PK and PD (efficacy)information determined for the antibody, as described in the Examplesherein for CA028_0496.g3 (bimekizumab). Typically a dosing regimen foruse in the present invention will provide a mean trough level of betweenaround 1 and 50 micro g/ml following single or multiple dose (steadystate), for example a mean trough level of greater than 10 micro g/ml.

Potential dose ranges and regimens for any of the embodiments describedherein include, but are not limited to, dosages ranging from 10 mg-1000mg unit doses (e.g., 8 mg, 16 mg, 32 mg, 40 mg, 64 mg, 80 mg, 160 mg,240 mg, 320 mg, 480 mg, 560 mg, or 640 mg), given every 1-10 weeks (byany route of administration, such as by as either a subcutaneous orintravenous administration). Optionally, a dose of neutralizing antibodyis administered every 1-20 weeks, for example every 2 weeks, every 3weeks, every 4 weeks, every 5 weeks, every 6 weeks, every 7 weeks, orevery 8-12 weeks (e.g., every 8 weeks, every 9 weeks, every 10 weeks,every 11 weeks, or every 12 weeks). The treatment period (i.e., theperiod of time during which one or more doses of antibody areadministered to a subject) may comprise at least two weeks, at leastfour weeks, at least eight weeks, at least 12 weeks, at least 16 weeks,at least 20 weeks, at least 24 weeks, at least 30 weeks, at least 36weeks, at least 40 weeks, at least 44 weeks, at least 48 weeks, at least52 weeks, or more. Any suitable number of doses may be administeredwithin the treatment period, such as the doses and time betweenadministrations described above. For example, one, two, three, or fourdoses of antibody are administered to a subject over, e.g., a 12 weektreatment period (optionally at week 0, week 4, week 8, and week 12). Inone exemplary embodiment, the method comprises administering 320 mg ofantibody to a subject every four weeks for at least twelve weeks. In oneexemplary embodiment, the method comprises administering 160 mg ofantibody to a subject every four weeks for at least twelve weeks. In oneexample the method comprises administering 160 mg, 240 mg or 320 mgevery four weeks. In one example the method comprises a 320 mg loadingdose followed by a maintenance dose of 160 mg or 240 mg every fourweeks. It will be appreciated that the doses may be given at theseintervals for a first treatment period, then given at a differentinterval for a second treatment period (e.g., administered every four oreight weeks for a first treatment period of, for example, 12 or 16 or 20weeks, then administered every eight, 12, or 16 weeks for a secondtreatment period lasting an additional, e.g., 24 or 36 weeks or more).

In some examples of the invention the dosage regimen used in an initialtreatment period, such as the first 12 or 16 or 24 weeks of treatment,may be considered an ‘induction period’, after which a differentregimen, such as a maintenance regimen, may be used in which typically alower dosage or reduced frequency of dosing may be used.

In some instances it may be possible to reduce the dosing frequencyand/or dose once a certain level of efficacy has been achieved. Forexample, in the method of treating psoriasis of the present invention,at week 12 or week 16 or week 24 the dosing frequency and/or dose may bechanged if the subject has achieved a PASI 75 or PASI 90. For example,in the method of treating psoriatic arthritis of the present invention,at week 12 or week 16 or week 24 the dosing frequency and/or dose may bechanged if the patient has achieved an ACR50. For example, in the methodof treating ankylosing spondylitis or nr-axSpa of the present invention,at week 12 or week 16 or week 24 the dosing frequency and/or dose may bechanged if the patient has achieved an ASAS40. Similarly in each ofthese examples, if at week 12 or week 16 or week 20 or week 24, thesubject has not achieved a desired clinical score, the dose and/ordosing frequency may be increased.

In various embodiments, including embodiments comprising treatingpsoriasis in a subject, an initial dose of antibody is administered thena subsequent dose of neutralizing antibody (such as CA028_0496.g3) isadministered 8-20 weeks (e.g., 8 weeks, 12 weeks, 16 weeks, or 20 weeks)after an initial administration. The subsequent dose may be the same asthe initial dose, an increased amount of neutralizing antibody, or adecreased amount of neutralizing antibody (i.e., a maintenance dose).Dosing with a neutralizing antibody described herein (e.g.,CA028_0496.g3 (Bimekizumab)) demonstrated rapid onset and remarkable,prolonged beneficial effect in humans, such as humans suffering frompsoriasis and psoriatic arthritis. For example, a single administrationof doses of 160 mg or more (e.g., 160 mg, 480 mg, and 640 mg) achievedclinically relevant and statistically significant differences fromplacebo in lesion severity score (LSS) and psoriasis area and severityindex (PASI) from week 2, with near-maximal improvements achieved byabout four to six weeks post-administration, which were maintained untilaround 16-20 weeks post-administration. In the 480 mg and 640 mg dosegroups, on average 83% of patients experienced PASI 90 from weeks 6-12and 90% at week 12. In subjects suffering from psoriatic arthritis,clinically relevant responses in disease activity measures were observedat 20 weeks following initial administration of neutralizing antibody(followed by two maintenance doses as described in Example 1).

An exemplary method of treating psoriatic arthritis provided by thedisclosure comprises administering to a subject an antibody describedherein using any one of the following dosage regimens: 16 mg every fourweeks, 160 mg every four weeks, 320 mg loading dose at week 0 followedby a maintenance dose of 160 mg every four weeks, and 320 mg every fourweeks. In one example, the method of treating psoriatic arthritisprovided by the disclosure comprises administering to a subject anantibody described herein using any one of the following dosageregimens: 160 mg every four weeks, 320 mg every four weeks, 320 mgloading dose at week 0 followed by a maintenance dose of 160 mg everyfour weeks or 320 mg loading dose at week 0 followed by a maintenancedose of 240 mg every four weeks. The treatment period can comprise,e.g., 12 weeks (for a total of at least three or four administrations ofantibody), 16 weeks, 24 weeks, or 48 weeks, or more. It will beappreciated that the doses may be given at these intervals for a firsttreatment period, then given at a different interval for a secondtreatment period (e.g., administered every four or eight weeks for afirst treatment period of, for example, 12 or 16 or 20 weeks, thenadministered every eight, 12, or 16 weeks for a second treatment periodlasting an additional, e.g., 24 or 36 weeks or more). For example, thedosage regimen, such as the dosing frequency, may change after a periodof time, such that in one example the antibody is administered using adosage regimen of 160 mg every four weeks until week 12, week 16 or week24 followed by 160 mg every eight weeks, starting at week 20, week 24 orweek 32 respectively. In one example the antibody is administered usinga dosage regimen of 320 mg every four weeks until week 12, week 16 orweek 24 followed by 320 mg every eight weeks starting at week 20, week24 or week 32 respectively. Optionally the dosage regimen, such asdosage amount, may change after a period of time, such that in oneexample the antibody is administered using a dosage regimen of 160 mg or320 mg every four weeks until week 12 or week 16 or week 24 followed bya dosage regimen of 320 mg or 160 mg every four weeks respectively.Optionally both the dosage amount and dosage frequency may change, suchthat in one example the antibody is administered using a dosage regimenof 160 mg every four weeks until week 12 or week 16 or week 24 followedby a dosage regimen of 320 mg every eight weeks.

In the case of psoriatic arthritis, it will be appreciated that thedosage regimen may differ depending on whether the subject hascoexistent psoriasis and/or a history of psoriasis or not. For example,the dosage regimen for psoriatic arthritis patients with coexistentmoderate to severe plaque psoriasis or a history of psoriasis maycomprise higher dosages and/or more frequent dosing than the dosageregimen for those subjects who do not have coexistent psoriasis and/or ahistory of psoriasis.

An exemplary method of treating psoriasis provided by the disclosurecomprises administering to a subject an antibody described herein usingany one of the following dosage regimens: 64 mg every four weeks, 160 mgevery four weeks or every 8 weeks, 320 mg every four weeks or everyeight weeks, 320 mg loading dose administered at week 0 followed bymaintenance doses of 160 mg every four weeks, or 480 mg every fourweeks. The doses may be given at these intervals over any suitabletreatment period such as at least four weeks, at least eight weeks, atleast 12 weeks, at least 16 weeks, at least 20 weeks, at least 24 weeks,at least 28 weeks, at least 30 weeks, at least 36 weeks, at least 40weeks, at least 44 weeks, at least 48 weeks, at least 52 weeks, or more.It will be appreciated that the doses may be given at these intervalsfor a first treatment period, then given at a different interval for asecond treatment period (e.g., administered every four or eight weeksfor a first treatment period of, for example, 12 or 16 or 20 or 24weeks, then administered every eight, 12, or 16 weeks for a secondtreatment period lasting an additional, e.g., 24 or 36 weeks). Forexample, the dosage regimen, such as the dosing frequency, may changeafter a period of time, such that in one example the antibody isadministered using a dosage regimen of 160 mg every four weeks untilweek 8, 12 or 16 followed by 160 mg every eight weeks, starting at week16, 20 or 24 respectively. In one example the antibody is administeredusing a dosage regimen of 320 mg every four weeks until week 8, 12 or 16followed by 320 mg every eight weeks starting at week 16, 20 or 24respectively. In one example the antibody is administered using a dosageregimen of 320 mg or 160 mg every four weeks until week 8, 12 or 16followed by 320 mg or 160 mg every twelve weeks. Optionally the dosageregimen, such as dosage amount, may change after a period of time, suchthat in one example the antibody is administered using a dosage regimenof 320 mg every four weeks until week 8 or week 12 followed by areduction to 160 mg every four weeks starting at week 12 or week 16respectively.

An exemplary method of treating ankylosing spondylitis or nr-axSpaprovided by the disclosure comprises administering to a subject anantibody described herein using any one of the following dosageregimens: 16 mg every four weeks, 160 mg every four weeks, 320 mgloading dose at week 0 followed by a maintenance dose of 160 mg everyfour weeks or 320 mg every four weeks. Preferably the dosage regimen is160 mg or 320 mg every four weeks. The treatment period can comprise,e.g., 12 weeks (for a total of at least three or four administrations ofantibody), 16 weeks, 24 weeks, or 48 weeks, or more. It will beappreciated that the doses may be given at these intervals for a firsttreatment period, then given at a different interval for a secondtreatment period (e.g., administered every four or eight weeks for afirst treatment period of, for example, 12 or 16, 20 or 24 weeks, thenadministered every eight, 12, or 16 weeks for a second treatment periodlasting an additional, e.g., 24 or 36 weeks or more). For example, thedosage regimen, such as frequency, may change after a period of time,such that in one example the antibody is administered using a dosageregimen of 160 mg every four weeks until week 12, 16 or 24 followed by160 mg every eight weeks. In one example the antibody is administeredusing a dosage regimen of 320 mg every four weeks until week 12, 16 or24 followed by 320 mg every eight weeks. Optionally the dosage regimen,such as dosage amount, may change after a period of time, such that inone example the antibody is administered using a dosage regimen of 160mg or 320 mg every four weeks until week 12 or week 16 or week 24followed by a dosage regimen of 320 mg or 160 mg every four weeksrespectively. Optionally both the dosage amount and dosage frequency maychange, such that in one example the antibody is administered using adosage regimen of 160 mg every four weeks until week 12 or week 16 orweek 24 followed by a dosage regimen of 320 mg every eight weeks.

Compositions may be administered individually to a patient or may beadministered in combination (e.g., simultaneously, sequentially orseparately) with other agents, drugs or hormones.

The dose at which the antibody molecule of the invention is administereddepends on the nature of the condition to be treated, the extent of theinflammation present and on whether the antibody molecule is being usedprophylactically or to treat an existing condition.

The frequency of dose will depend on the half-life of the antibodymolecule and the duration of its effect. If the antibody molecule has ashort half-life (e.g., 2 to 10 hours) it may be necessary to give one ormore doses per day. Alternatively, if the antibody molecule has a longhalf-life (e.g., 2 to 15 days) it may only be necessary to give a dosageonce per day, once per week or even once every 1 or 2 months.

It may be necessary to administer a loading dose followed by one or moremaintenance doses. The loading dose and maintenance doses may be thesame dosage amount, or they may be different. In one embodiment, themaintenance doses may be one-quarter, one-third, one-half, two-thirds,three-quarters, the same as, one and one-quarter, one and one-third, oneand one-half, one and two-thirds, one and three-quarters, double, ormore of the loading dose.

In one embodiment, the maintenance doses may be administered at aninterval after administration of the loading dose. This interval may beconsistent for each dose or may vary. This interval may be 1 day, 1week, 2 weeks, 3 weeks, 4 weeks, monthly, 6 weeks, 8 weeks, every othermonth, or at any other interval. In one embodiment, two maintenancedoses are administered every three weeks after a loading dose for atotal of three doses. In one embodiment, maintenance doses areadministered every four weeks.

The pharmaceutically acceptable carrier should not itself induce theproduction of antibodies harmful to the individual receiving thecomposition and should not be toxic. Suitable carriers may be large,slowly metabolised macromolecules such as proteins, polypeptides,liposomes, polysaccharides, polylactic acids, polyglycolic acids,polymeric amino acids, amino acid copolymers and inactive virusparticles.

Pharmaceutically acceptable salts can be used, for example mineral acidsalts, such as hydrochlorides, hydrobromides, phosphates and sulphates,or salts of organic acids, such as acetates, propionates, malonates andbenzoates.

Pharmaceutically acceptable carriers in therapeutic compositions mayadditionally contain liquids such as water, saline, glycerol andethanol. Additionally, auxiliary substances, such as wetting oremulsifying agents or pH buffering substances, may be present in suchcompositions. Such carriers enable the pharmaceutical compositions to beformulated as tablets, pills, dragees, capsules, liquids, gels, syrups,slurries and suspensions, for ingestion by the patient.

Preferred forms for administration include forms suitable for parenteraladministration, e.g., by injection or infusion, for example by bolusinjection or continuous infusion. Where the product is for injection orinfusion, it may take the form of a suspension, solution or emulsion inan oily or aqueous vehicle and it may contain formulatory agents, suchas suspending, preservative, stabilising and/or dispersing agents.Alternatively, the antibody molecule may be in dry form, forreconstitution before use with an appropriate sterile liquid.

Once formulated, the compositions of the invention can be administereddirectly to the subject. The subjects to be treated can be animals.However, it is preferred that the compositions are adapted foradministration to human subjects.

The pharmaceutical compositions of this invention may be administered byany number of routes including, but not limited to, oral, intravenous,intramuscular, intra-arterial, intramedullary, intrathecal,intraventricular, transdermal, transcutaneous (for example, see WO98/20734), subcutaneous, intraperitoneal, intranasal, enteral, topical,sublingual, intravaginal or rectal routes. Hyposprays may also be usedto administer the pharmaceutical compositions of the invention.Typically, the therapeutic compositions may be prepared as injectables,either as liquid solutions or suspensions. Solid forms suitable forsolution in, or suspension in, liquid vehicles prior to injection mayalso be prepared.

Direct delivery of the compositions will generally be accomplished byinjection, subcutaneously, intraperitoneally, intravenously orintramuscularly, or delivered to the interstitial space of a tissue. Thecompositions can also be administered into a lesion. Dosage treatmentmay be a single dose schedule or a multiple dose schedule. A preferredembodiment of the invention involves subcutaneous or intravenousadministration of the antibody.

It will be appreciated that the active ingredient in the compositionwill be an antibody molecule. As such, it will be susceptible todegradation in the gastrointestinal tract. Thus, if the composition isto be administered by a route using the gastrointestinal tract, thecomposition will need to contain agents which protect the antibody fromdegradation but which release the antibody once it has been absorbedfrom the gastrointestinal tract.

A thorough discussion of pharmaceutically acceptable carriers isavailable in Remington's Pharmaceutical Sciences (Mack PublishingCompany, N.J. 1991).

It is also envisaged that the antibody of the invention will beadministered by use of gene therapy. In order to achieve this, DNAcomprising nucleic acid sequences encoding the heavy and light chains ofthe antibody molecule under the control of appropriate DNA componentsare introduced into a patient such that the antibody chains areexpressed from the DNA sequences and assembled in situ.

In one embodiment, the formulation is provided as a formulation fortopical administrations including inhalation. Suitable inhalablepreparations include inhalable powders, metering aerosols containingpropellant gases or inhalable solutions free from propellant gases.Inhalable powders according to the disclosure containing the activesubstance may consist solely of the abovementioned active substances orof a mixture of the abovementioned active substances withphysiologically acceptable excipient. These inhalable powders mayinclude monosaccharides (e.g. glucose or arabinose), disaccharides (e.g.lactose, saccharose, maltose), oligo- and polysaccharides (e.g.dextranes), polyalcohols (e.g. sorbitol, mannitol, xylitol), salts (e.g.sodium chloride, calcium carbonate) or mixtures of these with oneanother. Mono- or disaccharides are suitably used, the use of lactose orglucose, particularly but not exclusively in the form of their hydrates.

Particles for deposition in the lung require a particle size less than10 microns, such as 1-9 microns, for example, from 0.1 to 5 microns, inparticular from 1 to 5 microns. The particle size of the activeingredient (such as the antibody or fragment) is of primary importance.

The propellant gases which can be used to prepare the inhalable aerosolsare known in the art. Suitable propellant gases are selected from amonghydrocarbons such as n-propane, n-butane or isobutane andhalohydrocarbons such as chlorinated and/or fluorinated derivatives ofmethane, ethane, propane, butane, cyclopropane or cyclobutane. Theabove-mentioned propellant gases may be used on their own or in mixturesthereof. Particularly suitable propellant gases are halogenated alkanederivatives selected from among TG 11, TG 12, TG 134a and TG227. Of theabovementioned halogenated hydrocarbons, TG134a(1,1,1,2-tetrafluoroethane) and TG227 (1,1,1,2,3,3,3-heptafluoropropane)and mixtures thereof are particularly suitable. Thepropellent-gas-containing inhalable aerosols may also contain otheringredients such as cosolvents, stabilisers, surface-active agents(surfactants), antioxidants, lubricants and means for adjusting the pH.All these ingredients are known in the art.

The propellant-gas-containing inhalable aerosols according to theinvention may contain up to 5% by weight of active substance. Aerosolsaccording to the invention contain, for example, 0.002 to 5% by weight,0.01 to 3% by weight, 0.015 to 2% by weight, 0.1 to 2% by weight, 0.5 to2% by weight or 0.5 to 1% by weight of active ingredient.

Alternatively topical administrations to the lung may also be byadministration of a liquid solution or suspension formulation, forexample employing a device such as a nebulizer, for example, a nebulizerconnected to a compressor (e.g., the Pari LC-Jet Plus® nebulizerconnected to a Pari Master® compressor manufactured by Pari RespiratoryEquipment, Inc., Richmond, Va.).

The antibody of the invention can be delivered dispersed in a solvent,e.g., in the form of a solution or a suspension. It can be suspended inan appropriate physiological solution, e.g., saline or otherpharmacologically acceptable solvent or a buffered solution. Bufferedsolutions known in the art may contain 0.05 mg to 0.15 mg disodiumedetate, 8.0 mg to 9.0 mg NaCl, 0.15 mg to 0.25 mg polysorbate, 0.25 mgto 0.30 mg anhydrous citric acid, and 0.45 mg to 0.55 mg sodium citrateper 1 ml of water so as to achieve a pH of about 4.0 to 5.0. Asuspension can employ, for example, lyophilised antibody.

The therapeutic suspensions or solution formulations can also containone or more excipients. Excipients are well known in the art and includebuffers (e.g., citrate buffer, phosphate buffer, acetate buffer andbicarbonate buffer), amino acids, urea, alcohols, ascorbic acid,phospholipids, proteins (e.g., serum albumin), EDTA, sodium chloride,liposomes, mannitol, sorbitol, and glycerol. Solutions or suspensionscan be encapsulated in liposomes or biodegradable microspheres. Theformulation will generally be provided in a substantially sterile formemploying sterile manufacture processes.

This may include production and sterilization by filtration of thebuffered solvent/solution used for the formulation, aseptic suspensionof the antibody in the sterile buffered solvent solution, and dispensingof the formulation into sterile receptacles by methods familiar to thoseof ordinary skill in the art.

Nebulizable formulation according to the present disclosure may beprovided, for example, as single dose units (e.g., sealed plasticcontainers or vials) packed in foil envelopes. Each vial contains a unitdose in a volume, e.g., 2 mL, of solvent/solution buffer.

The invention has been described by way of example only, is in no waymeant to be limiting, and that modifications of detail can be madewithin the scope of the claims hereinafter. Preferred features of eachembodiment of the invention are as for each of the other embodimentsmutatis mutandis. All publications, including but not limited to patentsand patent applications, cited in this specification are hereinincorporated by reference as if each individual publication werespecifically and individually indicated to be incorporated by referenceherein as though fully set forth.

EXAMPLES Example 1—Clinical Trial of CA028 0496.g3 (UCB4940 orBimekizumab): Loading Dose and Maintenance Doses

In one embodiment, an early proof-of-concept, investigator blind,placebo-controlled study evaluating the safety, pharmacokinetics andpharmacodynamics of multiple doses of CA028_0496.g3 in subjects withpsoriatic arthritis has been performed. This is identified as UCB studyPA0007.

The study comprised four active dose arms and placebo administeredintravenously as an infusion on three occasions given every three weeks:Cohort 1 (240 mg loading dose at week 0 followed by 160 mg at week 3 andweek 6 [N=20 (active), 3 placebo]; Cohort 2 (80 mg loading dose at week0 followed by 40 mg at week 3 and week 6)[N=6 (active), 3 placebo];Cohort 3 (160 mg loading dose at week 0, followed by 80 mg at week 3 andweek 6), N=6 (active), 3 placebo; Cohort 4 (560 mg loading dose at week0, followed by 320 mg at week 3 and week 6), N=6 (active), 3 placebo.

The objectives of this study included the safety, tolerability andpharmacokinetics of multiple-dose administration of CA028_0496.g3 insubjects with psoriatic arthritis. The objectives also included theevaluation of the effect of multiple-dose administration ofCA028_0496.g3 on the severity of psoriatic arthritis in the joints(American College of Rheumatology (“ACR”) 20/50/70 response) and, forskin, the clinical features of plaque psoriasis (Psoriasis Area andSeverity Index (“PASI”) 50/75/90 response). ACR score is a scale thatmeasures improvement in joint effects associated with psoriaticarthritis and rheumatoid arthritis, and improvements in ACR score arealso associated with the treatment of rheumatoid arthritis.

Patient Population: All eligible subjects were required to be at least18 years of age and have a diagnosis of adult-onset psoriatic arthritismade at least 6 months prior to screening for the study as defined bythe classification criteria for psoriatic arthritis (“CASPAR”) criteria(i.e., inflammatory articular disease (joint, spine or entheseal) and >3points of the 5 CASPAR categories). The CASPAR criteria used may befound in Figure [2]. Subjects were also required to have activepsoriatic lesions or a history of psoriatic lesions. In terms of jointinvolvement, subjects were required to have active arthritis as definedby: ≥3 tender joints at screening and baseline, ≥3 swollen joints atscreening and baseline, and fulfilling at least one of the followingduring screening (either ESR ≥28 mm/hour or CRP≥3 mg/L). Subjects wereall inadequate responders to at least one non-biologic disease-modifyingantirheumatic drug (“DMARD”) and/or 1 approved biologic DMARD. Subjectsmust have been taking concurrent methotrexate at the start of treatmentfor at least 3 months, and be on a stable dose at least 4 weeks prior tobaseline. Subjects who were intolerant to methotrexate may have beeneligible if they had received non-steroidal anti-inflammatory drugs(NSAIDs) and/or steroids for at least 8 weeks and were on a stable doseat least 4 weeks prior to baseline.

Study Disposition: 50 subjects completed all doses of the study, ofwhich 38 subjects received at least one dose of the investigationalmedicinal product, CA028_0496.g3. Including subjects who receivedplacebo, a total of 48 subjects formed the overall analysis data set astwo subjects were excluded for being potentially un-blinded at the site.

Clinical Outcomes: Clinically significant effects were observed for bothjoints and skin at week 8 from start of treatment:

Skin Effects: 23 subjects had skin involvement at baseline, with bodysurface area (BSA) ≥3% and a mean baseline PASI of 15.9 (SD=14.6). Only22 subjects were in the analysis data set due to missed dosing by onesubject. Results on skin effects are described in Figure [3a] and Figure[3b]. Onset of response was rapid for both skin and joints. Out of theeligible subjects for skin assessment, for the combined top 3 doses, aPASI75 response of 100% was observed at week 8 from start of treatment,and a PASI90 response of 87% and appear to have been maintained untilthe end of the study at week 20 post-start of treatment. In contrast, inthe Future 1 trial for Secukinumab in psoriatic arthritis, the observedPASI75 response at week 24 was 64.8% and PASI 90 response at week 24 was49%. (Glottieb A B et al. Arthritis Rheum. 2014, 66(Suppl 11):S233;Mease P et al. Ann Rheum Dis. 2014; 73(1):48-55.) This is furtherdepicted in Figure [4].

Joint Effects: Results on joint effects are described in FIGS. [5 a]-[5d]. An 80% ACR20 response, a 40% ACR50 response and a 23% ACR70 responsewere observed at week 8 from start of treatment was observed for thecombined top 3 doses of the group. The ACR20 response appeared to besustained at this level through to week 20 (day 140), albeit with anincreased placebo response (see FIG. 5 b-5 d ). Following week 8 (2weeks after the last dose) background medication was un-controlled.

The time to maximum ACR50 and 70 responses took longer (post week 12),with responses of 56.7% and 36.7% by week 20, respectively. In contrast,in the Future 1 trial for Secukinumab in psoriatic arthritis, theobserved ACR20 response at week 24 was 50%. Mease P et al., 2014,Arthritis Rheum., 66(Suppl 11):S423-S424; Mease P et al., 2014, AnnRheum Dis., 73(1):48-55. This is further depicted in Figure [6].

Bayesian Analysis: A Bayesian analysis of ACRn(tr) at week 8 from startof treatment was performed using a Gaussian-likelihood model with aninformative prior on the placebo group. An assessment of the equality ofthe treatment effect size as well as homogeneity of variances wasperformed and it was deemed to be appropriate to pool the top threedoses together for CA028_0496.g3. The informed prior on the placebogroup for ACRn(tr) was estimated by using data from a previous Cimzia®study in psoriatic arthritis (PsA001, A phase 3, multicenter,randomized, double-blind, parallel-group, placebo-controlled study toevaluate the efficacy and safety of certolizumab pegol in subjects withadult-onset active and progressive psoriatic arthritis.).

The Bayesian analysis indicated strong statistical evidence(probability >99%) that CA028_0496.g3 achieves higher values of ACRn(tr)compared to placebo. Furthermore, the probability that the mediantreatment difference in ACRn(tr) compared to placebo is greater than0.31 (difference observed in previous Cimzia® studies) was more than 99%in the pooled CA028_0496.g3 top 3 doses group.

For ACR20 response, a Bayesian analysis was performed at Week 8 poststart of dosing using a logistic model with an informative prior on theplacebo group. The informed prior for the placebo group on ACR20 wasestimated using data from a previous Cimzia® study (PsA001).

The Bayesian analysis indicated that the probability of CA028_0496.g3inducing greater ACR20 response rates than placebo was over 99% for thepooled CA028_0496.g3 top 3 doses groups. In addition, there was a >99%probability that the median treatment difference in ACR20 compared toplacebo is greater than 25% (difference observed in PsA001) for thepooled top 3 doses of CA028_0496.g3. These results are presented inFigure [7].

The validity of these results in terms of benchmarking against otherbiological therapies (anti-TNFs and IL17As and anti-IL12/23) inpsoriatic arthritis was made by comparing with literature data for ACR20response at week 8. (Adalimumab, Golimumab, Secukinumab and Ustekinumab,see Figure [8]), ensuring overall concordance in the results. Inconclusion, a high posterior probability (>99%) for observed effects onACR20 response is greater than anti-TNFs or anti-IL-17As at week 8 inthis PA0007.

Pharmacokinetic-Pharmacodynamic Targeting: In order to achieve thepharmacologically active dose levels to achieve the desired clinicaleffects, four active dosing arms were selected. The aim was to achievetrough concentrations over the first 8 week period of 10× the Ec50(derived from mild psoriasis response in UP0008 described in Example 2)of approximately 10 pg/mL and higher. The results of this study areincluded in Figure [9]. In UP0008, bimekizumab demonstrateddose-proportional PK (half-life of about 22 days).

Predicted Sub-Cutaneous Dosing: A bioavailability study (RA0124) wasconducted for CA028_0496.g3 to evaluate the pharmacokinetics ofCA028_0496.g3 following subcutaneous administrations of 80 mg and 160 mgdoses compared to 160 mg given by i.v. The results indicate that basedon the principles of super-position, it should be possible to achievethe target concentrations of CA028_0496.g3 summarized in Figure [9](achieved in PA0007) via monthly subcutaneous doses of 160 mg orgreater, such as 320 mg, using a Q4W regimen (Figure [10]) or via a 320mg loading dose followed by a 160 mg Q4W regimen.

Example 2—Clinical Trial of CA028 0496.g3 (UCB4940 or Bimekizumab):Single Dose

UP0008 is a single ascending dose Phase 1 study (NCT02529956) of thesafety of intravenously administered CA028_0496.g3 in subjects with mildto moderate psoriasis affecting ≤5% body surface area (BSA). Inclusioncriteria included, e.g., male or female (≥18 to ≤70 years), confirmeddiagnosis of mild-to-moderate plaque-type psoriasis for ≥6 monthsinvolving ≤5% of body surface area (excluding the scalp), and ≥2psoriatic lesions with ≥1 plaques in suitable biopsy sites. Exclusioncriteria included, e.g., use of systemic non-biologic psoriasis therapy(methotrexate, cyclophosphamide) or psoralen plus ultravioletA/ultraviolet A phototherapy within 4 weeks prior to screening,treatment with biologic agents ≤12 months before the study, and use orplanned use of live attenuated vaccines 6 weeks of screening. A total of39 patients received a single i.v. dose of bimekizumab (8-640 mg) orplacebo (randomized, double-blind).

Five dosages were employed: 8 mg, 40 mg, 160, mg, 480 mg, and 640 mg.Following single-dose administration, bimekizumab (8-640 mg) was welltolerated and no patient discontinued due to treatment-emergent AEs; nosevere AEs were reported. Indeed, doses of up to 640 mg (approximately 8mg/kg body weight) have been well tolerated to date in UP0008.

After administration, bimekizumab produced improvements across theevaluated clinical features of plaque psoriasis, LSS, PASI and PGA (FIG.14 ). A fast onset of response was observed with a reduction of >80%from baseline LSS in the top two dose cohorts at study Week 2. For doses160, 480, and 640 mg (N=6 each), clinically-relevant and statisticallysignificant differences from placebo (N=13) were observed in lesionseverity score (LSS) (Figure [11]) and psoriasis area and severity index(PASI) from week 2 (Figure [12]), with near-maximal improvementsobserved by week 4.

Specifically with respect to LSS, the magnitude of response wasreflected by a maximal reduction in mean change from baseline in LSSof >90% in the 160 mg group. This was achieved by Week 8 anddemonstrated durability, being maintained to Week 16. In the 480 mgcohort a maximal magnitude of response, 100%, was achieved as early asWeek 4. The response also was durable, being maintained to Week 16. Inthe 640 mg cohort, the maximal reduction (100%) was achieved by Week 8and was durable, being maintained between Weeks 12 and 20 (FIG. 14A). Inaddition to the 640 mg cohort, no overlap in CIs between the otherbimekizumab cohorts (40-480 mg) at Week 2 vs placebo was observed,indicating a difference between the two cohorts. Similar results wereobtained for the area under the effect curve (Weeks 0-4, [AUEC0-4w])variable (data not shown).

With respect to PASI, a fast onset of response was observed with areduction of >65% from baseline PASI scores in the top two cohorts atWeek 2. Bayesian analysis revealed that the posterior probability of≥60% improvement over placebo at this time point was >80%. For thebimekizumab 160 mg cohort, the magnitude of response was reflected by amaximal reduction in the mean change from baseline in PASI score of >85%achieved by Week 6. This response was durable, being maintained to studyWeek 12. In the 480 mg and 640 mg cohorts, a maximal magnitude ofresponse of ≥94% was observed. This was achieved by Week 6 in the 480 mgcohort and Week 4 in the 640 mg cohort. In both cohorts the response wasdurable, being maintained to Week 12 (FIG. 5 b ). Additionally, forbimekizumab 40-640 mg cohorts at Week 2, the posterior probability ofa >0% improvement in PASI score over placebo was 99%.

The significant level of improvement (as indicated by LSS percent changeand PASI percent change from baseline) was maintained until the finaltimepoint measured—20 weeks. In the top two dose groups, 83% of patientsexperienced PASI 90 (a 90% improvement in PASI score), from weeks 6-12and 90% at week 12 (Figure [13]). At the top three doses, 100% ofpatients achieved PASI75, and 53% achieved PASI100.

PGA (Physicians Global Assessment) also was assessed using a seven-pointscale (0=clear, 6=severe). See Figure [14]. A reduction of >50% frombaseline in PGA was observed at the highest doses of bimekizumab (480 mgand 640 mg) assessed. Maximal reductions in mean change from baseline inPGA scores of >75% were observed in the bimekizumab 160 mg cohort. Thisreduction was achieved by Week 6 and was durable, being maintained toWeek 12.

Maximal reductions in mean change from baseline in PGA scores were 100%and 94%, respectively for bimekizumab 480 mg and 640 mg cohorts (FIG. 5c ). These reductions were achieved by Week 8 and were durable, beingmaintained to Week 12 in the 480 mg cohort, and achieved by Week 4 andmaintained to Week 12 in the 640 mg cohort.

Example 3—Anti-IL17A/F Antibody Down Regulates Bone Formation Processes

Prototypical phenotypic subsets of spondyloarthritis are ankylosingspondylitis (AS) for axial disease and psoriatic arthritis (PsA) for thecombination of peripheral arthritis with psoriasis. Individual patientsoften display multi-system disease; a significant proportion of patientswith AS exhibit skin psoriasis and a significant proportion of patientswith PsA develop axial disease. AS and PsA share a common geneticbackground, familial aggregation of the different subforms, sharedhistopathological findings, and similar responses to therapy (e.g.,efficacy of TNF blockade and IL-17A blockade in both AS and PsA andfailure of B cell depleting therapy and IL-6 blockade in AS as well asPsA). The results described herein with respect to psoriatic arthritissuggest therefore that anti-IL-17A/F antibodies may also be effective inthe treatment of ankylosing spondylitis.

Pathological bone formation associated with the spondyloarthropathies(SpA) is a major cause of structural tissue damage resulting inpermanent patient disability. Patients with AS experience excessive boneformation on the periosteal surface near joints and intervertebralspaces, resulting in bone spurs that fuse joints and aggrevate tendonand ligament insertion sites, causing pain and limited mobilityassociated with the disease. Previous studies using recombinant IL-17Aand IL-17F revealed divergent effects in osteogenic differentiation.Osta et al., Frontiers in Immunology 5, (2014), have demonstrated thatIL-17 positively influences osteogenic differentiation in humanmesenchymal stem cells (hMSCs). In agreement, Huang et al, Cell DeathDiffer. 16, 1332-43 (2009) have reported that IL-17 stimulatesproliferation and osteogenic differentiation of hMSCs. In addition,Croes et al. Bone 84, 262-270 (2016), demonstrated osteogenicstimulation of hMSCs with IL-17A and IL-17F over a range ofconcentrations. Conversely, others demonstrated that IL-17 inhibited theosteogenic differentiation of rat calvarial cells, mouse MSCs and adulthuman MSCs, and implicated that IL-17 was pro-osteogenic. See, e.g.,Chang et al., Proc. Natl. Acad. Sci. U.S.A. 110, 9469-74 (2013); Nam etal., PLoS One 7, e40044 (2012).

This Example demonstrates that an anti-IL-17A/F monoclonal antibody(CA028_0496.g3 (Bimekizumab)) reduced biomarkers associated withperiosteal stem cell osteogenic differentiation in vitro, reduced matrixmineralization, and reduced bone nodule formation in vitro,demonstrating that an anti-IL-17A/F monoclonal antibody (CA028_0496.g3(Bimekizumab)) is likely to be effective in treating (e.g., slowing theprogression of, reducing the symptoms of) AS.

Methodology: As the periosteum gives rise to reparative tissues forfracture repair, a human periosteal stem cell model (Eyckmans et al.,Biomaterials 34, 4612-21 (2013)) was employed to probe the IL-17 axis inthe context of pathological bone formation. Periosteum was harvestedfrom patients undergoing lower limb orthopedic surgery, as previouslydescribed. Roberts et al., Biomaterials 32, 4393-4405 (2011); Roberts etal., Stem Cell Res. 7, 137-144 (2011). Adherent human periosteum derivedstem cells (hPDSCs) were enzymatically released from the matrix andexpanded in growth media (DMEM medium supplemented with 10% fetal bovineserum, 1% sodium pyruvate, 1% antibiotics and antimycotics). For invitro osteogenic differentiation assays, passage 6 hPDSCs were seeded at3000 cells/cm² in 24-well plates to allow quantification of geneexpression and mineralization in response to TH-17 supernatant exposure.These cultures were incubated with TH-17 supernatant (1:50 dilution)containing vehicle (PBS) or anti-IL-17A, anti-IL-17F, or anti-IL-17A/Fantibody (10 g/ml) in combination with an osteogenic growth factorcocktail (GFC); 10 ng/ml TGF-β1 (Peprotech), 20 ng/ml EGF (Invitrogen),10 ng/ml IL-6 (Peprotech), 3 mM Ca²⁺ ions and 2 mM PO₄ ⁻ (prepared inHEPES buffered saline) as previously described. Chai et al., Tissue Eng.Part A 17, 1083-1097 (2011). IL-6 was replaced (GFC-IL-6) with TH-17supernatants in test conditions as an inflammatory trigger fordifferentiation. The mixtures were incubated in a shaking water-bath for1 hour at 37° C. to allow for efficient neutralization of the IL-17isoforms. Each condition was applied to the relevant hPDSC monolayerevery other day until the end of culture period at day 8. Monolayerswere either fixed in 10% neutral buffered formalin or stained with 1%alizarin red to measure deposited mineral, or lysed to isolate total RNAfor osteogenic marker gene expression analysis. Prior to fixation,monolayers were visualised using standard microscopy techniques and theappearance of bone nodules was visually assessed.

To examine the effect of human serum from AS patients on hPDSC IL-17mediated signalling, 10,000 cells/cm² cells were seeded in 24 wellplates. The following day the media was removed and the monolayers werewashed with sterile warmed PBS, following which the media was replacedwith DMEM containing either 10% healthy human serum (HS) or AS patientserum (SRSC01, SRSC03, SRSC04, SRSC05, SRSC06 and SRSC07) with 1% sodiumpyruvate and 1% antibiotics/antimycotics. The monolayers were incubatedfor 48 hours after which the media were discarded and monolayersterminated for total RNA isolation. Subsequently, expression of thedownstream target gene IL-6 and osteogenic marker RUNX2 were evaluated.

Total RNA extraction, cDNA synthesis and qPCR: Monolayers were lysedusing the RNeasy mini kit according to the kit instructions (Qiagen).Complementary DNA (cDNA) was synthesized by reverse transcription of 500ng of total RNA using the high capacity cDNA reverse transcription kit(Applied Biosciences) under the following thermal cycling conditions;25° C. for 10 mins, 37° C. for 120 mins and 85° C. for 5 minutes. Toquantify the level of gene transcripts within each sample, primers(designed using Primer3 Plus, NCBI) were combined with iTaq universalSYBR green supermix (Biorad) and 10 ng cDNA, subsequently 10 μL aliquotswere applied to Hard-Shell® 96-Well PCR Plates (Biorad). Thermal cyclingconditions were as follows: 10 min at 95° C., with 40 cycles of 15 s at950 C, 30 s at 60° C., and 20 s at 72° C., on a Bio-Rad CFX1000Real-Time System. Each run consisted of melt curve analysis andtemplate-free controls to confirm specific, single productamplification. All primer pairs produced single amplicons and reactionswere of similar efficiency (95-100%), as established by standarddilution curve and analysis. Target gene quantification was achievedusing the 2-ΔΔCT method described by Livak et al, relative to HPRT1.

IL-17A and IL-17F measurement by ELISA: IL-17A and IL-17F protein wasmeasured in patient serum from AS patients using sandwich ELISA(Peprotech, London, UK). AS patient blood was isolated in BD VacutainerSST tubes in the Rheumatology clinic at the Royal National OrthopaedicHospital (Stanmore, UK). The NHS Research Ethics Committee approved allprocedures. Following collection, the blood was centrifuged at 1000 gfor 10 minutes at room temperature. The separated serum was thenfiltered through a 0.2-μm membrane. Aliquots of serum were stored at−80° C. prior to analysis. A 1:2 dilution of each AS patient serum wasperformed in diluent buffer provided in the human IL-17A and IL-17F ABTSkits (Peprotech, London, UK) prior to analysis to reduce effects ofserum matrix. Measurement of IL-17A and IL-17F was performed as per kitinstructions.

Results: Utilising a biomimetic osteogenic assay (described inInternational Patent Publication WO2013189975), TH-17 supernatant(TH-17SN) was either treated with or without the inclusion of monoclonalantibodies directed towards IL-17A, IL-17F, or IL-17A/F. Osteogenictranscripts such as RUNX2, SP7 and BMP2 were analysed alongside markersof osteogenic matrix formation (BGLAP) and mineralisation (PHOSPHO1), inaddition to assessment of the extent of mineralisation by alizarin redstaining and assessment of the appearance of bone nodules. TH-17 cellsupernatant potently enhanced hPDSC osteogenic differentiation andmineralisation (p<0.01). Both IL-6 expression and in vitro boneformation were blocked by neutralisation of IL-17A, IL-17F and IL-17A/Fin the inflammatory milieu, with neutralisation of IL-17A/F exhibitingthe largest effect. FIGS. 15A-G. Also, the appearance of bone noduleswere visibly less in anti-IL-17A/F treated samples compared to treatmentwith anti-IL-17A or anti-IL-17F alone.

The presence of IL-17A and IL-17F in the serum of patients presentingwith AS was quantified by ELISA. Both IL-17A and IL-17F proteins weremeasured in six patients and compared to the level in healthy humanserum (HS). Varying levels of IL-17A and IL-17F were identifiable acrossthe different patients with significantly greater levels of both IL-17Aand IL-17F in three patients (P<0.01) compared to healthy human serumcontrol group. Serum from patient samples from the remaining threepatients appeared to exhibit similar IL-17A, however greater IL-17Fexpression in one patient compared to HAS control. To investigate therelevance of this, hPDSCs were treated with AS patient serum andincubated for 48 hours. The down-stream target IL-6 and osteogenicmarker RUNX2 were elevated. To define the importance of IL-17A andIL-17F in the expression of these markers, hPDSCs were treated withserum from AS patients (serum samples that exhibited significantlyhigher levels of both IL-17A and IL-17F and stimulated IL-6 and RUNX2mRNA expression) following pre-incubation with either control IgGantibody or antibodies specific to IL-17A, IL-17F or IL-17A/F. Theresults indicated that blocking both IL-17A and IL-17F resulted inpotent and significant decreases in IL-6 and RUNX2 mRNA expression. Thiseffect was greatest with the antibody that had high affinity forIL-17A/F. FIGS. 16A & 16B.

Discussion: Inflammatory and degenerative joint diseases frequentlyelicit proliferative responses of the periarticular periosteal bone,leading to the formation of bony spurs (osteophytes). In inflammatorydiseases such as AS, enthesophytes originate at the tendon insertionsite (entheses) in peripheral joint and the vertebral bodies. It ishypothesized that the progenitor cells within the periosteum areintimately involved with this bone forming process and can lead toankylosis with impairment of motion and joint dysfunction. The resultsdescribed herein demonstrate that both IL-17A and IL-17F enhance invitro osteogenic differentiation and bone formation from hPDSCs.Neutralization of IL-17A and IL-17F via a monoclonal antibody that bindsboth IL-17A/F (CA028_0496.g3 (Bimekizumab)) inhibited IL-6 geneexpression and abrogated osteogenic gene (RUNX2, SP7, and BMP2)expression. CA028_0496.g3 also significantly mediated bone matrixmineralization effectors (BGLAP and PHOSPHO1), resulting in anobservable reduction in matrix mineralization and bone nodule formation.Neutralization of IL-17A/F resulted in greatest inhibition of osteogenicdifferentiation markers and matrix mineralization compared toneutralization of IL-17A or IL-17F alone). Current therapeutics displaylimited efficacy in blocking enthesophyte formation; hence, thematerials and methods described herein present a significant technicaladvantage for blocking this debilitating tissue morbidity.

1. A method of treating psoriatic arthritis in a human comprising thestep of administering to the human a neutralizing antibody which bindshuman IL-17A and human IL-17F.
 2. The method of claim 1, wherein theantibody specifically binds (a) an epitope of human IL-17F, the epitopecomprising one or more residues selected from ARG47, ARG73, LEU75 andILE86 of SEQ ID NO: 27; and/or (b) epitope of human IL-17A, the epitopecomprising one or more residues selected from TYR44, ASN45, ARG46,TRP51, ASN52, HIS54 and ASP84 of SEQ ID NO:
 28. 3. (canceled)
 4. Themethod of claim 1, wherein the antibody binds to the same epitope onhuman IL-17A, human IL-17F, or IL-17 A/F heterodimer as a neutralisingantibody that has a heavy chain comprising the sequence given in SEQ IDNO: 11 and a light chain comprising the sequence given in SEQ ID NO: 10.5. The method of claim 1, wherein the antibody cross-blocks aneutralising antibody that has a heavy chain comprising the sequencegiven in SEQ ID NO: 11 and a light chain comprising the sequence givenin SEQ ID NO: 10 and binds human IL-1 7A and human IL-1 7F.
 6. Themethod of claim 1, wherein the antibody comprises a light chain variabledomain and a heavy chain variable domain, wherein the variable domain ofthe light chain comprises the sequence given in SEQ ID NO:10.
 7. Themethod of claim 1, wherein the antibody is bimekizumab.
 8. The method ofany one of claims 1 through 7, wherein the antibody is administered as apharmaceutical composition.
 9. The method of any one of claims 1 through8, wherein the antibody is administered subcutaneously.
 10. The methodof any one of claims 1 through 8, wherein the antibody is administeredintravenously.
 11. The method of claim 1, wherein the human (a) has adiagnosis of adult-onset psoriatic arthritis; (b) has active arthritis;(c) has active psoriatic lesions or a history of psoriatic lesions;and/or (d) is an inadequate responder to at least one non-biologicdisease-modifying antirheumatic drug (“DMARD”) and/or one approvedbiologic DMARD. 12-17. (canceled)
 18. A method of treating psoriaticarthritis in a human concurrently treated with methotrexate comprisingthe step of administering to the human a neutralizing antibody whichbinds human IL-17A and human IL-17F.
 19. (canceled)
 20. The method ofclaim 1, wherein the antibody is administered in an amount that iseffective to provide an ACR20 response at week 8, an ACR50 response atweek 8, or an ACR70 response at week 8 in a population of patients inneed of treatment. 21-22. (canceled)
 23. The method of claim 1, whereinthe antibody is administered in an amount that is effective to provide aPASI50 response at week 8, a PASI75 response at week 8, or a PASI90response at week
 8. 24.-30. (canceled)
 31. A method of reducing jointeffects in a human comprising the step of administering to the human aneutralizing antibody which binds human IL-17A and human IL-17F. 32.(canceled)
 33. A method of reducing psoriasis and reducing joint effectsin a human comprising the step of administering to the human aneutralizing antibody which binds human IL-17A and human IL-17F.
 34. Themethod of claim 33, wherein the psoriasis is plaque psoriasis. 35.(canceled)
 36. A method of treating psoriatic arthritis in a human,comprising the step of administering to the human at least one dose of aneutralizing antibody which binds human IL-17A and human IL-17F.
 37. Amethod of treating rheumatoid arthritis in a human comprising the stepof administering to the human a neutralizing antibody which binds humanIL-17A and human IL-17F.
 38. The method of claim 37, wherein the humanhas a diagnosis of adult-onset rheumatoid arthritis. 39-41. (canceled)42. The method of claim 37, wherein the human (a) has active arthritis;and/or (b) is an inadequate responder to at least one non-biologicdisease-modifying antirheumatic drug (“DMARD”) and/or one approvedbiologic DMARD.
 43. (canceled)
 44. A method of treating rheumatoidarthritis in a human concurrently treated with methotrexate comprisingthe step of administering to the human a neutralizing antibody whichbinds human IL-17A and human IL-17F. 45-58. (canceled)
 59. The method ofclaim 1, wherein the method comprises administering a dose comprisingbetween 40 and 640 mg of the antibody. 60-71. (canceled)
 72. The methodof claim 1, comprising administering to the human a loading dose of theneutralizing antibody followed by at least one maintenance dose of theantibody. 73-82. (canceled)
 83. The method of treating psoriaticarthritis of claim 1 wherein the method comprises administering (a) 16mg of antibody every four weeks, (b) 160 mg of antibody every fourweeks, (b) 320 mg loading dose of antibody followed by a maintenancedose of 160 mg of antibody every four weeks, or (d) 320 mg of antibodyevery four weeks. 84-112. (canceled)
 113. A method of treatingankylosing spondylitis in a human comprising the step of administeringto the human a neutralizing antibody which binds human IL-17A and humanIL-17F. 114-124. (canceled)